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Sample records for histone tail charges

  1. Computer Modeling Reveals that Modifications of the Histone Tail Charges Define Salt-Dependent Interaction of the Nucleosome Core Particles

    OpenAIRE

    Yang, Ye; Lyubartsev, Alexander P.; Korolev, Nikolay; Nordenskiöld, Lars

    2009-01-01

    Coarse-grained Langevin molecular dynamics computer simulations were conducted for systems that mimic solutions of nucleosome core particles (NCPs). The NCP was modeled as a negatively charged spherical particle representing the complex of DNA and the globular part of the histones combined with attached strings of connected charged beads modeling the histone tails. The size, charge, and distribution of the tails relative to the core were built to match real NCPs. Three models of NCPs were con...

  2. Computer modeling reveals that modifications of the histone tail charges define salt-dependent interaction of the nucleosome core particles.

    Science.gov (United States)

    Yang, Ye; Lyubartsev, Alexander P; Korolev, Nikolay; Nordenskiöld, Lars

    2009-03-18

    Coarse-grained Langevin molecular dynamics computer simulations were conducted for systems that mimic solutions of nucleosome core particles (NCPs). The NCP was modeled as a negatively charged spherical particle representing the complex of DNA and the globular part of the histones combined with attached strings of connected charged beads modeling the histone tails. The size, charge, and distribution of the tails relative to the core were built to match real NCPs. Three models of NCPs were constructed to represent different extents of covalent modification on the histone tails: (nonmodified) recombinant (rNCP), acetylated (aNCP), and acetylated and phosphorylated (paNCP). The simulation cell contained 10 NCPs in a dielectric continuum with explicit mobile counterions and added salt. The NCP-NCP interaction is decisively dependent on the modification state of the histone tails and on salt conditions. Increasing the monovalent salt concentration (KCl) from salt-free to physiological concentration leads to NCP aggregation in solution for rNCP, whereas NCP associates are observed only occasionally in the system of aNCPs. In the presence of divalent salt (Mg(2+)), rNCPs form dense stable aggregates, whereas aNCPs form aggregates less frequently. Aggregates are formed via histone-tail bridging and accumulation of counterions in the regions of NCP-NCP contacts. The paNCPs do not show NCP-NCP interaction upon addition of KCl or in the presence of Mg(2+). Simulations for systems with a gradual substitution of K(+) for Mg(2+), to mimic the Mg(2+) titration of an NCP solution, were performed. The rNCP system showed stronger aggregation that occurred at lower concentrations of added Mg(2+), compared to the aNCP system. Additional molecular dynamics simulations performed with a single NCP in the simulation cell showed that detachment of the tails from the NCP core was modest under a wide range of salt concentrations. This implies that salt-induced tail dissociation of the

  3. Structural genomics of histone tail recognition.

    Science.gov (United States)

    Wang, Minghua; Mok, Man Wai; Harper, Hong; Lee, Wen Hwa; Min, Jinrong; Knapp, Stefan; Oppermann, Udo; Marsden, Brian; Schapira, Matthieu

    2010-10-15

    The structural genomics of histone tail recognition web server is an open access resource that presents within mini articles all publicly available experimental structures of histone tails in complex with human proteins. Each article is composed of interactive 3D slides that dissect the structural mechanism underlying the recognition of specific sequences and histone marks. A concise text html-linked to interactive graphics guides the reader through the main features of the interaction. This resource can be used to analyze and compare binding modes across multiple histone recognition modules, to evaluate the chemical tractability of binding sites involved in epigenetic signaling and design small molecule inhibitors. http://www.thesgc.org/resources/histone_tails/ matthieu.schapira@utoronto.ca Supplementary data are available at Bioinformatics online.

  4. Nucleosome Dancing at the Tempo of Histone Tail Acetylation

    Directory of Open Access Journals (Sweden)

    Angélique Galvani

    2015-07-01

    Full Text Available The impact of histone acetylation on transcription was revealed over 50 years ago by Allfrey and colleagues. However, it took decades for an understanding of the fine mechanism by which this posttranslational modification affects chromatin structure and promotes transcription. Here, we review breakthroughs linking histone tail acetylation, histone dynamics, and transcription. We also discuss the histone exchange during transcription and highlight the important function of a pool of non-chromatinized histones in chromatin dynamics.

  5. Nucleosome Dancing at the Tempo of Histone Tail Acetylation.

    Science.gov (United States)

    Galvani, Angélique; Thiriet, Christophe

    2015-07-15

    The impact of histone acetylation on transcription was revealed over 50 years ago by Allfrey and colleagues. However, it took decades for an understanding of the fine mechanism by which this posttranslational modification affects chromatin structure and promotes transcription. Here, we review breakthroughs linking histone tail acetylation, histone dynamics, and transcription. We also discuss the histone exchange during transcription and highlight the important function of a pool of non-chromatinized histones in chromatin dynamics.

  6. Nucleosome Dancing at the Tempo of Histone Tail Acetylation

    OpenAIRE

    Angélique Galvani; Christophe Thiriet

    2015-01-01

    The impact of histone acetylation on transcription was revealed over 50 years ago by Allfrey and colleagues. However, it took decades for an understanding of the fine mechanism by which this posttranslational modification affects chromatin structure and promotes transcription. Here, we review breakthroughs linking histone tail acetylation, histone dynamics, and transcription. We also discuss the histone exchange during transcription and highlight the important function of a pool of non-chroma...

  7. The Role of Histone Tails in the Nucleosome: A Computational Study

    Science.gov (United States)

    Erler, Jochen; Zhang, Ruihan; Petridis, Loukas; Cheng, Xiaolin; Smith, Jeremy C.; Langowski, Jörg

    2014-01-01

    Histone tails play an important role in gene transcription and expression. We present here a systematic computational study of the role of histone tails in the nucleosome, using replica exchange molecular dynamics simulations with an implicit solvent model and different well-established force fields. We performed simulations for all four histone tails, H4, H3, H2A, and H2B, isolated and with inclusion of the nucleosome. The results confirm predictions of previous theoretical studies for the secondary structure of the isolated tails but show a strong dependence on the force field used. In the presence of the entire nucleosome for all force fields, the secondary structure of the histone tails is destabilized. Specific contacts are found between charged lysine and arginine residues and DNA phosphate groups and other binding sites in the minor and major DNA grooves. Using cluster analysis, we found a single dominant configuration of binding to DNA for the H4 and H2A histone tails, whereas H3 and H2B show multiple binding configurations with an equal probability. The leading stabilizing contribution for those binding configurations is the attractive interaction between the positively charged lysine and arginine residues and the negatively charged phosphate groups, and thus the resulting charge neutralization. Finally, we present results of molecular dynamics simulations in explicit solvent to confirm our conclusions. Results from both implicit and explicit solvent models show that large portions of the histone tails are not bound to DNA, supporting the complex role of these tails in gene transcription and expression and making them possible candidates for binding sites of transcription factors, enzymes, and other proteins. PMID:25517156

  8. Histone H3 tail clipping regulates gene expression

    OpenAIRE

    Santos-Rosa, Helena; Kirmizis, Antonis; Nelson, Christopher; Bartke, Till; Saksouk, Nehme; Cote, Jacques; Kouzarides, Tony

    2008-01-01

    Induction of gene expression in yeast and human cells involves changes in histone modifications associated with promoters. Here we identify a histone H3 endopeptidase activity in S. cerevisiae that may regulate these events. The endopeptidase cleaves H3 after alanine 21, generating a histone lacking the first 21 residues and displays a preference for H3 tails carrying repressive modifications. In vivo, the H3 N-terminus is clipped, specifically within the promoter of genes following the induc...

  9. In vitro targeting reveals intrinsic histone tail specificity of the Sin3/histone deacetylase and N-CoR/SMRT corepressor complexes.

    NARCIS (Netherlands)

    Vermeulen, M.; Carrozza, MJ; Lasonder, E.; Workman, JL; Logie, C.; Stunnenberg, H.G.

    2004-01-01

    The histone code is among others established via differential acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). To unambiguously determine the histone tail specificity of HDAC-containing complexes, we have established an in vitro system consisting of

  10. Influence of histone tails and H4 tail acetylations on nucleosome-nucleosome interactions.

    Science.gov (United States)

    Liu, Ying; Lu, Chenning; Yang, Ye; Fan, Yanping; Yang, Renliang; Liu, Chuan-Fa; Korolev, Nikolay; Nordenskiöld, Lars

    2011-12-16

    Nucleosome-nucleosome interaction plays a fundamental role in chromatin folding and self-association. The cation-induced condensation of nucleosome core particles (NCPs) displays properties similar to those of chromatin fibers, with important contributions from the N-terminal histone tails. We study the self-association induced by addition of cations [Mg(2+), Ca(2+), cobalt(III)hexammine(3+), spermidine(3+) and spermine(4)(+)] for NCPs reconstituted with wild-type unmodified histones and with globular tailless histones and for NCPs with the H4 histone tail having lysine (K) acetylations or lysine-to-glutamine mutations at positions K5, K8, K12 and K16. In addition, the histone construct with the single H4K16 acetylation was investigated. Acetylated histones were prepared by a semisynthetic native chemical ligation method. The aggregation behavior of NCPs shows a general cation-dependent behavior similar to that of the self-association of nucleosome arrays. Unlike nucleosome array self-association, NCP aggregation is sensitive to position and nature of the H4 tail modification. The tetra-acetylation in the H4 tail significantly weakens the nucleosome-nucleosome interaction, while the H4 K→Q tetra-mutation displays a more modest effect. The single H4K16 acetylation also weakens the self-association of NCPs, which reflects the specific role of H4K16 in the nucleosome-nucleosome stacking. Tailless NCPs can aggregate in the presence of oligocations, which indicates that attraction also occurs by tail-independent nucleosome-nucleosome stacking and DNA-DNA attraction in the presence of cations. The experimental data were compared with the results of coarse-grained computer modeling for NCP solutions with explicit presence of mobile ions. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Contribution of histone N-terminal tails to the structure and stability of nucleosomes.

    Science.gov (United States)

    Iwasaki, Wakana; Miya, Yuta; Horikoshi, Naoki; Osakabe, Akihisa; Taguchi, Hiroyuki; Tachiwana, Hiroaki; Shibata, Takehiko; Kagawa, Wataru; Kurumizaka, Hitoshi

    2013-01-01

    Histones are the protein components of the nucleosome, which forms the basic architecture of eukaryotic chromatin. Histones H2A, H2B, H3, and H4 are composed of two common regions, the "histone fold" and the "histone tail". Many efforts have been focused on the mechanisms by which the post-translational modifications of histone tails regulate the higher-order chromatin architecture. On the other hand, previous biochemical studies have suggested that histone tails also affect the structure and stability of the nucleosome core particle itself. However, the precise contributions of each histone tail are unclear. In the present study, we determined the crystal structures of four mutant nucleosomes, in which one of the four histones, H2A, H2B, H3, or H4, lacked the N-terminal tail. We found that the deletion of the H2B or H3 N-terminal tail affected histone-DNA interactions and substantially decreased nucleosome stability. These findings provide important information for understanding the complex roles of histone tails in regulating chromatin structure.

  12. Charge State of the Globular Histone Core Controls Stability of the Nucleosome

    Science.gov (United States)

    Fenley, Andrew T.; Adams, David A.; Onufriev, Alexey V.

    2010-01-01

    Presented here is a quantitative model of the wrapping and unwrapping of the DNA around the histone core of the nucleosome that suggests a mechanism by which this transition can be controlled: alteration of the charge state of the globular histone core. The mechanism is relevant to several classes of posttranslational modifications such as histone acetylation and phosphorylation; several specific scenarios consistent with recent in vivo experiments are considered. The model integrates a description based on an idealized geometry with one based on the atomistic structure of the nucleosome, and the model consistently accounts for both the electrostatic and nonelectrostatic contributions to the nucleosome free energy. Under physiological conditions, isolated nucleosomes are predicted to be very stable (38 ± 7 kcal/mol). However, a decrease in the charge of the globular histone core by one unit charge, for example due to acetylation of a single lysine residue, can lead to a significant decrease in the strength of association with its DNA. In contrast to the globular histone core, comparable changes in the charge state of the histone tail regions have relatively little effect on the nucleosome's stability. The combination of high stability and sensitivity explains how the nucleosome is able to satisfy the seemingly contradictory requirements for thermodynamic stability while allowing quick access to its DNA informational content when needed by specific cellular processes such as transcription. PMID:20816070

  13. Posttranslational Modifications of the Histone 3 Tail and Their Impact on the Activity of Histone Lysine Demethylases In Vitro

    DEFF Research Database (Denmark)

    Lohse, Brian; Helgstrand, Charlotte; Andersson, Jan Legaard

    2013-01-01

    Posttranslational modifications (PTMs) of the histone H3 tail such as methylation, acetylation and phosphorylation play important roles in epigenetic signaling. Here we study the effect of some of these PTMs on the demethylation rates of methylated lysine 9 in vitro using peptide substrates...... mimicking histone H3. Various combinations with other PTMs were employed to study possible cross-talk effects by comparing enzyme kinetic characteristics. We compared the kinetics of histone tail substrates for truncated histone lysine demethylases KDM4A and KDM4C containing only the catalytic core (cc...... are significantly influenced by other PTMs on the same peptide, and emphasizes the importance of studying these interactions at the peptide level to get a more detailed understanding of the dynamics of epigenetic marks....

  14. Recognition Elements in the Histone H3 and H4 Tails for Seven Different Importins.

    Science.gov (United States)

    Soniat, Michael; Cağatay, Tolga; Chook, Yuh Min

    2016-09-30

    N-terminal tails of histones H3 and H4 are known to bind several different Importins to import the histones into the cell nucleus. However, it is not known what binding elements in the histone tails are recognized by the individual Importins. Biochemical studies of H3 and H4 tails binding to seven Importins, Impβ, Kapβ2, Imp4, Imp5, Imp7, Imp9, and Impα, show the H3 tail binding more tightly than the H4 tail. The H3 tail binds Kapβ2 and Imp5 with KD values of 77 and 57 nm, respectively, and binds the other five Importins more weakly. Mutagenic analysis shows H3 tail residues 11-27 to be the sole binding segment for Impβ, Kapβ2, and Imp4. However, Imp5, Imp7, Imp9, and Impα bind two separate elements in the H3 tail: the segment at residues 11-27 and an isoleucine-lysine nuclear localization signal (IK-NLS) motif at residues 35-40. The H4 tail also uses either one or two basic segments to bind the same set of Importins with a similar trend of relative affinities as the H3 tail, albeit at least 10-fold weaker. Of the many lysine residues in the H3 and H4 tails, only acetylation of the H3 Lys14 substantially decreased binding to several Importins. Lastly, we show that, in addition to the N-terminal tails, the histone fold domains of H3 and H4 and/or the histone chaperone Asf1b are important for Importin-histone recognition. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Recognition Elements in the Histone H3 and H4 Tails for Seven Different Importins*

    Science.gov (United States)

    Soniat, Michael; Cağatay, Tolga; Chook, Yuh Min

    2016-01-01

    N-terminal tails of histones H3 and H4 are known to bind several different Importins to import the histones into the cell nucleus. However, it is not known what binding elements in the histone tails are recognized by the individual Importins. Biochemical studies of H3 and H4 tails binding to seven Importins, Impβ, Kapβ2, Imp4, Imp5, Imp7, Imp9, and Impα, show the H3 tail binding more tightly than the H4 tail. The H3 tail binds Kapβ2 and Imp5 with KD values of 77 and 57 nm, respectively, and binds the other five Importins more weakly. Mutagenic analysis shows H3 tail residues 11–27 to be the sole binding segment for Impβ, Kapβ2, and Imp4. However, Imp5, Imp7, Imp9, and Impα bind two separate elements in the H3 tail: the segment at residues 11–27 and an isoleucine-lysine nuclear localization signal (IK-NLS) motif at residues 35–40. The H4 tail also uses either one or two basic segments to bind the same set of Importins with a similar trend of relative affinities as the H3 tail, albeit at least 10-fold weaker. Of the many lysine residues in the H3 and H4 tails, only acetylation of the H3 Lys14 substantially decreased binding to several Importins. Lastly, we show that, in addition to the N-terminal tails, the histone fold domains of H3 and H4 and/or the histone chaperone Asf1b are important for Importin-histone recognition. PMID:27528606

  16. Double chromodomains cooperate to recognize the methylated histone H3 tail

    Energy Technology Data Exchange (ETDEWEB)

    Flanagan, John F.; Mi, Li-Zhi; Chruszcz, Maksymilian; Cymborowski, Marcin; Clines, Katrina L.; Kim, Youngchang; Minor, Wladek; Rastinejad, Fraydoon; Khorasanizadeh, Sepideh (ANL/SBC); (UV)

    2010-07-19

    Chromodomains are modules implicated in the recognition of lysine-methylated histone tails and nucleic acids. CHD (for chromo-ATPase/helicase-DNA-binding) proteins regulate ATP-dependent nucleosome assembly and mobilization through their conserved double chromodomains and SWI2/SNF2 helicase/ATPase domain. The Drosophila CHD1 localizes to the interbands and puffs of the polytene chromosomes, which are classic sites of transcriptional activity. Other CHD isoforms (CHD3/4 or Mi-2) are important for nucleosome remodelling in histone deacetylase complexes. Deletion of chromodomains impairs nucleosome binding and remodelling by CHD proteins. Here we describe the structure of the tandem arrangement of the human CHD1 chromodomains, and its interactions with histone tails. Unlike HP1 and Polycomb proteins that use single chromodomains to bind to their respective methylated histone H3 tails, the two chromodomains of CHD1 cooperate to interact with one methylated H3 tail. We show that the human CHD1 double chromodomains target the lysine 4-methylated histone H3 tail (H3K4me), a hallmark of active chromatin. Methylammonium recognition involves two aromatic residues, not the three-residue aromatic cage used by chromodomains of HP1 and Polycomb proteins. Furthermore, unique inserts within chromodomain 1 of CHD1 block the expected site of H3 tail binding seen in HP1 and Polycomb, instead directing H3 binding to a groove at the inter-chromodomain junction.

  17. Characterization of Complete Histone Tail Proteoforms Using Differential Ion Mobility Spectrometry

    DEFF Research Database (Denmark)

    Shliaha, Pavel V; Baird, Matthew A; Nielsen, Mogens M

    2017-01-01

    Histone proteins are subject to dynamic post-translational modifications (PTMs) that cooperatively modulate the chromatin structure and function. Nearly all functional PTMs are found on the N-terminal histone domains (tails) of ∼50 residues protruding from the nucleosome core. Using high-definition...... differential ion mobility spectrometry (FAIMS) with electron transfer dissociation, we demonstrate rapid baseline gas-phase separation and identification of tails involving monomethylation, trimethylation, acetylation, or phosphorylation in biologically relevant positions. These are by far the largest variant...

  18. Asymmetric breathing motions of nucleosomal DNA and the role of histone tails.

    Science.gov (United States)

    Chakraborty, Kaushik; Loverde, Sharon M

    2017-08-14

    The most important packing unit of DNA in the eukaryotic cell is the nucleosome. It undergoes large-scale structural re-arrangements during different cell cycles. For example, the disassembly of the nucleosome is one of the key steps for DNA replication, whereas reassembly occurs after replication. Thus, conformational dynamics of the nucleosome is crucial for different DNA metabolic processes. We perform three different sets of atomistic molecular dynamics simulations of the nucleosome core particle at varying degrees of salt conditions for a total of 0.7 μs simulation time. We find that the conformational dynamics of the nucleosomal DNA tails are oppositely correlated from each other during the initial breathing motions. Furthermore, the strength of the interaction of the nucleosomal DNA tail with the neighboring H2A histone tail modulates the conformational state of the nucleosomal DNA tail. With increasing salt concentration, the degree of asymmetry in the conformation of the nucleosomal DNA tails decreases as both tails tend to unwrap. This direct correlation between the asymmetric breathing motions of the DNA tails and the H2A histone tails, and its decrease at higher salt concentrations, may play a significant role in the molecular pathway of unwrapping.

  19. Asymmetric breathing motions of nucleosomal DNA and the role of histone tails

    Science.gov (United States)

    Chakraborty, Kaushik; Loverde, Sharon M.

    2017-08-01

    The most important packing unit of DNA in the eukaryotic cell is the nucleosome. It undergoes large-scale structural re-arrangements during different cell cycles. For example, the disassembly of the nucleosome is one of the key steps for DNA replication, whereas reassembly occurs after replication. Thus, conformational dynamics of the nucleosome is crucial for different DNA metabolic processes. We perform three different sets of atomistic molecular dynamics simulations of the nucleosome core particle at varying degrees of salt conditions for a total of 0.7 μs simulation time. We find that the conformational dynamics of the nucleosomal DNA tails are oppositely correlated from each other during the initial breathing motions. Furthermore, the strength of the interaction of the nucleosomal DNA tail with the neighboring H2A histone tail modulates the conformational state of the nucleosomal DNA tail. With increasing salt concentration, the degree of asymmetry in the conformation of the nucleosomal DNA tails decreases as both tails tend to unwrap. This direct correlation between the asymmetric breathing motions of the DNA tails and the H2A histone tails, and its decrease at higher salt concentrations, may play a significant role in the molecular pathway of unwrapping.

  20. Distinct Roles of Histone H3 and H2A Tails in Nucleosome Stability

    Science.gov (United States)

    Li, Zhenhai; Kono, Hidetoshi

    2016-01-01

    Nucleosome breathing potentially increases the DNA exposure, which in turn recruits DNA-binding protein and regulates gene transcription. Numerous studies have shown the critical roles of N-terminal tails of histones H3 and H4 in gene expression; however, few studies have focused on the H2A C-terminal tail. Here we present thorough computational studies on a single nucleosome particle showing the linker DNA closing and opening, which is thought to be nucleosome breathing. With our simulation, the H2A C-terminal and H3 N-terminal tails were found to modulate the nucleosome conformation differently. The H2A C-terminal tail regulates nucleosome conformation by binding to linker DNA at different locations, whereas the H3 N-terminal tail regulates linker DNA by binding to it in different patterns. Further MD simulation on tail truncated structures corroborates this analysis. These findings replenish our understanding of the histone tail regulation mechanism on atomic level. PMID:27527579

  1. PR-Set7 establishes a repressive trans-tail histone code that regulates differentiation.

    Science.gov (United States)

    Sims, Jennifer K; Rice, Judd C

    2008-07-01

    Posttranslational modifications of the DNA-associated histone proteins play fundamental roles in eukaryotic transcriptional regulation. We previously discovered a novel trans-tail histone code involving monomethylated histone H4 lysine 20 (H4K20) and H3 lysine 9 (H3K9); however, the mechanisms that establish this code and its function in transcription were unknown. In this report, we demonstrate that H3K9 monomethylation is dependent upon the PR-Set7 H4K20 monomethyltransferase but independent of its catalytic function, indicating that PR-Set7 recruits an H3K9 monomethyltransferase to establish the trans-tail histone code. We determined that this histone code is involved in a transcriptional regulatory pathway in vivo whereby monomethylated H4K20 binds the L3MBTL1 repressor protein to repress specific genes, including RUNX1, a critical regulator of hematopoietic differentiation. The selective loss of monomethylated H4K20 at the RUNX1 promoter resulted in the displacement of L3MBTL1 and a concomitant increase in RUNX1 transcription. Importantly, the lack of monomethylated H4K20 in the human K562 multipotent cell line was specifically associated with spontaneous megakaryocytic differentiation, in part, by activating RUNX1. Our findings demonstrate that this newly described repression pathway is required for regulating proper megakaryopoiesis and suggests that it is likely to function similarly in other multipotent cell types to regulate specific differentiation pathways.

  2. Corecognition of DNA and a methylated histone tail by the MSL3 chromodomain

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Daesung; Blus, Bartlomiej J.; Chandra, Vikas; Huang, Pengxiang; Rastinejad, Fraydoon; Khorasanizadeh, Sepideh (UVHS)

    2010-11-12

    MSL3 resides in the MSL (male-specific lethal) complex, which upregulates transcription by spreading the histone H4 Lys16 (H4K16) acetyl mark. We discovered a DNA-dependent interaction of MSL3 chromodomain with the H4K20 monomethyl mark. The structure of a ternary complex shows that the DNA minor groove accommodates the histone H4 tail, and monomethyllysine inserts in a four-residue aromatic cage in MSL3. H4K16 acetylation antagonizes MSL3 binding, suggesting that MSL function is regulated by a combination of post-translational modifications.

  3. A combinatorial H4 tail library for exploring the histone code.

    Science.gov (United States)

    Garske, Adam L; Craciun, Gheorghe; Denu, John M

    2008-08-05

    Histone modifications modulate chromatin structure and function. A posttranslational modification-randomized, combinatorial library based on the first 21 residues of histone H4 was designed for systematic examination of proteins that interpret a histone code. The 800-member library represented all permutations of most known modifications within the N-terminal tail of histone H4. To determine its utility in a protein binding assay, the on-bead library was screened with an antibody directed against phosphoserine 1 of H4. Among the hits, 59 of 60 sequences were phosphorylated at S1, while 30 of 30 of those selected from the nonhits were unphosphorylated. A 512-member version of the library was then used to determine the binding specificity of the double tudor domain of hJMJD2A, a histone demethylase involved in transcriptional repression. Global linear least-squares fitting of modifications from the identified peptides (40 hits and 34 nonhits) indicated that methylation of K20 was the primary determinant for binding, but that phosphorylation and acetylation of neighboring sites attenuated the interaction. To validate the on-bead screen, isothermal titration calorimetry was performed with 13 H4 peptides. Dissociation constants ranged from 1 mM to 1 microM and corroborated the screening results. The general approach should be useful for probing the specificity of any histone-binding protein.

  4. Role of histone tails in the conformation and interactions of nucleosome core particles.

    Science.gov (United States)

    Bertin, Aurélie; Leforestier, Amélie; Durand, Dominique; Livolant, Françoise

    2004-04-27

    The goal of this work was to test the role of the histone tails in the emergence of attractive interactions between nucleosomes above a critical salt concentration that corresponds to the complete tail extension outside the nucleosome [Mangenot, S., et al (2002) Biophys. J. 82, 345-356; Mangenot, S., et al (2002) Eur. Phys. J. E 7, 221-231]. Small angle X-ray scattering experiments were performed in parallel with intact and trypsin tail-deleted nucleosomes with 146 +/- 3 bp DNA. We varied the monovalent salt concentration from 10 to 300 monovalent salt concentration and followed the evolution of (i) the second virial coefficient that characterizes the interactions between particles and (ii) the conformation of the particle. The attractive interactions do not emerge in the absence of the tails, which validates the proposed hypothesis.

  5. Hyperglycemia Induces a Dynamic Cooperativity of Histone Methylase and Demethylase Enzymes Associated With Gene-Activating Epigenetic Marks That Coexist on the Lysine Tail

    National Research Council Canada - National Science Library

    Daniella Brasacchio; Jun Okabe; Christos Tikellis; Aneta Balcerczyk; Prince George; Emma K. Baker; Anna C. Calkin; Michael Brownlee; Mark E. Cooper; Assam El-Osta

    2009-01-01

    Hyperglycemia Induces a Dynamic Cooperativity of Histone Methylase and Demethylase Enzymes Associated With Gene-Activating Epigenetic Marks That Coexist on the Lysine Tail Daniella Brasacchio 1 , Jun...

  6. The histone H3 N-terminal tail: a computational analysis of the free energy landscape and kinetics.

    Science.gov (United States)

    Zheng, Yuqing; Cui, Qiang

    2015-05-28

    Histone tails are the short peptide protrusions outside of the nucleosome core particle and they play a critical role in regulating chromatin dynamics and gene activity. A histone H3 N-terminal tail, like other histone tails, can be covalently modified on different residues to activate or repress gene expression. Previous studies have indicated that, despite its intrinsically disordered nature, the histone H3 N-terminal tail has regions of notable secondary structural propensities. To further understand the structure-dynamics-function relationship in this system, we have carried out 75.6 μs long implicit solvent simulations and 29.3 μs long explicit solvent simulations. The extensive samplings allow us to better characterize not only the underlying free energy landscape but also kinetic properties through Markov state models (MSM). Dihedral principal component analysis (dPCA) and locally scaled diffusion map (LSDMap) analysis yield consistent results that indicate an overall flat free energy surface with several shallow basins that correspond to conformations with a high α-helical propensity in two regions of the peptide. Kinetic information extracted from Markov state models reveals rapid transitions between different metastable states with mean first passage times spanning from several hundreds of nanoseconds to hundreds of microseconds. These findings shed light on how the dynamical nature of the histone H3 N-terminal tail is related to its function. The complementary nature of dPCA, LSDMap and MSM for the analysis of biomolecules is also discussed.

  7. Med5(Nut1 and Med17(Srb4 are direct targets of mediator histone H4 tail interactions.

    Directory of Open Access Journals (Sweden)

    Zhongle Liu

    Full Text Available The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone tail peptides substituted with an amino acid analog that is a UV activatible crosslinker, we have identified specific subunits within Mediator that participate in histone tail interactions. Using Mediator purified from mutant yeast strains we have evaluated the impact of these subunits on histone tail binding. This analysis has identified the Med5 subunit of Mediator as a target for histone tail interactions and suggests that the previously observed effect of med5 mutations on telomeric heterochromatin and silencing is direct.

  8. Regulation of Nucleosome Stacking and Chromatin Compaction by the Histone H4 N-Terminal Tail-H2A Acidic Patch Interaction.

    Science.gov (United States)

    Chen, Qinming; Yang, Renliang; Korolev, Nikolay; Liu, Chuan Fa; Nordenskiöld, Lars

    2017-06-30

    Chromatin folding and dynamics are critically dependent on nucleosome-nucleosome interactions with important contributions from internucleosome binding of the histone H4 N-terminal tail K16-R23 domain to the surface of the H2A/H2B dimer. The H4 Lys16 plays a pivotal role in this regard. Using in vitro reconstituted 12-mer nucleosome arrays, we have investigated the mechanism of the H4 N-terminal tail in maintaining nucleosome-nucleosome stacking and mediating intra- and inter-array chromatin compaction, with emphasis on the role of K16 and the positive charge region, R17-R23. Analytical ultracentrifugation sedimentation velocity experiments and precipitation assays were employed to analyze effects on chromatin folding and self-association, respectively. Effects on chromatin folding caused by various mutations and modifications at position K16 in the H4 histone were studied. Additionally, using charge-quenching mutations, we characterized the importance of the interaction of the residues within the H4 positive charge region R17-R23 with the H2A acidic patch of the adjacent nucleosome. Furthermore, crosslinking experiments were conducted to establish the proximity of the basic tail region to the acidic patch. Our data indicate that the positive charge and length of the side chain of H4 K16 are important for its access to the adjacent nucleosome in the process of nucleosome-nucleosome stacking and array folding. The location and orientation of the H4 R17-R23 domain on the H2A/H2B dimer surface of the neighboring nucleosome core particle (NCP) in the compacted chromatin fiber were established. The dominance of electrostatic interactions in maintaining intra-array interaction was demonstrated. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. H3 Histone Tail Conformation within the Nucleosome and the Impact of K14 Acetylation Studied Using Enhanced Sampling Simulation

    Science.gov (United States)

    Ikebe, Jinzen; Sakuraba, Shun; Kono, Hidetoshi

    2016-01-01

    Acetylation of lysine residues in histone tails is associated with gene transcription. Because histone tails are structurally flexible and intrinsically disordered, it is difficult to experimentally determine the tail conformations and the impact of acetylation. In this work, we performed simulations to sample H3 tail conformations with and without acetylation. The results show that irrespective of the presence or absence of the acetylation, the H3 tail remains in contact with the DNA and assumes an α-helix structure in some regions. Acetylation slightly weakened the interaction between the tail and DNA and enhanced α-helix formation, resulting in a more compact tail conformation. We inferred that this compaction induces unwrapping and exposure of the linker DNA, enabling DNA-binding proteins (e.g., transcription factors) to bind to their target sequences. In addition, our simulation also showed that acetylated lysine was more often exposed to the solvent, which is consistent with the fact that acetylation functions as a post-translational modification recognition site marker. PMID:26967163

  10. [Histone variants and histone exchange].

    Science.gov (United States)

    Wu, Nan; Gui, Jian-Fang

    2006-04-01

    Histones, as the basic components of nucleosome, are essential to chromatin structure and function. To adapt to various states of chromatin, corresponding histone variants are incorporated in nucleosome, and certain modifications also occur on the variants' tails. These variants change the conformation and stability of nucleosome to facilitate transcriptional activation or deactivation, DNA repairing, heterochromatin formation, and others. During histone exchange, chromatin remodeling complex facilitates histone variant deposition into nucleosome, and different variants have diverse deposition pathways. Recently, research on histone variants is not only a new hotspot in epigenetics, but also a new annotation of "histone code". In addition, histone exchange reveals new changing mechanism of DNA-histone interaction.

  11. Nucleosome–nucleosome interactions via histone tails and linker DNA regulate nuclear rigidity

    Science.gov (United States)

    Shimamoto, Yuta; Tamura, Sachiko; Masumoto, Hiroshi; Maeshima, Kazuhiro

    2017-01-01

    Cells, as well as the nuclei inside them, experience significant mechanical stress in diverse biological processes, including contraction, migration, and adhesion. The structural stability of nuclei must therefore be maintained in order to protect genome integrity. Despite extensive knowledge on nuclear architecture and components, however, the underlying physical and molecular mechanisms remain largely unknown. We address this by subjecting isolated human cell nuclei to microneedle-based quantitative micromanipulation with a series of biochemical perturbations of the chromatin. We find that the mechanical rigidity of nuclei depends on the continuity of the nucleosomal fiber and interactions between nucleosomes. Disrupting these chromatin features by varying cation concentration, acetylating histone tails, or digesting linker DNA results in loss of nuclear rigidity. In contrast, the levels of key chromatin assembly factors, including cohesin, condensin II, and CTCF, and a major nuclear envelope protein, lamin, are unaffected. Together with in situ evidence using living cells and a simple mechanical model, our findings reveal a chromatin-based regulation of the nuclear mechanical response and provide insight into the significance of local and global chromatin structures, such as those associated with interdigitated or melted nucleosomal fibers. PMID:28428255

  12. Characterization of structural variability sheds light on the specificity determinants of the interaction between effector domains and histone tails.

    Science.gov (United States)

    Lois, Sergi; Akizu, Naiara; de Xaxars, Gemma Mas; Vázquez, Iago; Martínez-Balbás, Marian; de la Cruz, Xavier

    2010-02-16

    Structural characterization of the interaction between histone tails and effector modules (bromodomains, chromodomains, PHD fingers, etc.) is fundamental to understand the mechanistic aspects of epigenetic regulation of gene expression. In recent years many researchers have applied this approach to specific systems, thus providing a valuable but fragmentary view of the histone-effector interaction. In our work we use this information to characterize the structural features of the two main components of this interaction, histone peptides and the binding site of effector domains (focusing on those which target modified lysines), and increase our knowledge on its specificity determinants. Our results show that the binding sites of effectors are structurally variable, but some clear trends allow their classification in three main groups: flat-groove, narrow-groove and cavity-insertion. In addition, we found that even within these classes binding site variability is substantial. These results in context with the work from other researchers indicate that the there are at least two determinants of binding specificity in the binding site of effector modules. Finally, our analysis of the histone peptides sheds light on the structural transition experienced by histone tails upon effector binding, showing that it may vary depending on the local properties of the sequence stretch considered, thus allowing us to identify an additional specificity determinant for this interaction. Overall, the results of our analysis contribute to clarify the origins of specificity: different regions of the binding site and, in particular, differences in the disorder-order transitions experienced by different histone sequence stretches upon binding.

  13. The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects.

    Science.gov (United States)

    Arita, Adriana; Shamy, Magdy Y; Chervona, Yana; Clancy, Harriet A; Sun, Hong; Hall, Megan N; Qu, Qingshan; Gamble, Mary V; Costa, Max

    2012-06-01

    The precise mechanisms by which nickel and arsenic compounds exert their carcinogenic properties are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of compounds of these two metals. In vitro exposure to certain nickel or arsenic compounds induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males when compared with females in the arsenic population. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells. Copyright © 2012 Elsevier GmbH. All rights reserved.

  14. THE EFFECT OF EXPOSURE TO CARCINOGENIC METALS ON HISTONE TAIL MODIFICATIONS AND GENE EXPRESSION IN HUMAN SUBJECTS

    Science.gov (United States)

    Arita, Adriana; Shamy, Magdy Y.; Chervona, Yana; Clancy, Harriet A.; Sun, Hong; Hall, Megan N.; Qu, Qingshan; Gamble, Mary V.; Costa, Max

    2013-01-01

    The precise mechanisms for the carcinogenesis of nickel and arsenic compounds are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of these two metal compounds. In vitro exposure to nickel or arsenic induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males compared to females. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells. PMID:22633395

  15. Head-tail instability and Landau damping in bunches with space charge

    Directory of Open Access Journals (Sweden)

    V. Kornilov

    2010-11-01

    Full Text Available Head-tail modes in bunches with space charge are studied using particle tracking simulations. The eigenfrequencies and eigenfunctions of transverse coherent oscillations in a Gaussian bunch are determined and compared with theories. A model for an airbag distribution in a barrier potential gives good predictions for the head-tail spectrum and for eigenfunctions in bunches with space charge. Using numerical simulations, space-charge induced Landau damping in a bunch is demonstrated. The damping rates are quantified for different modes and space-charge tune shifts. Finally, the head-tail instability with space charge is studied for the resistive-wall impedance below the mode coupling threshold. Results demonstrate that space-charge induced damping can suppress the instability for moderately strong space charge; instability growth rates saturate at strong space charge, in agreement with theoretical predictions.

  16. The amino-terminal tails of histones H2A and H3 coordinate efficient base excision repair, DNA damage signaling and postreplication repair in Saccharomyces cerevisiae

    Science.gov (United States)

    Meas, Rithy; Smerdon, Michael J.; Wyrick, John J.

    2015-01-01

    Histone amino-terminal tails (N-tails) are required for cellular resistance to DNA damaging agents; therefore, we examined the role of histone N-tails in regulating DNA damage response pathways in Saccharomyces cerevisiae. Combinatorial deletions reveal that the H2A and H3 N-tails are important for the removal of MMS-induced DNA lesions due to their role in regulating the basal and MMS-induced expression of DNA glycosylase Mag1. Furthermore, overexpression of Mag1 in a mutant lacking the H2A and H3 N-tails rescues base excision repair (BER) activity but not MMS sensitivity. We further show that the H3 N-tail functions in the Rad9/Rad53 DNA damage signaling pathway, but this function does not appear to be the primary cause of MMS sensitivity of the double tailless mutants. Instead, epistasis analyses demonstrate that the tailless H2A/H3 phenotypes are in the RAD18 epistasis group, which regulates postreplication repair. We observed increased levels of ubiquitylated PCNA and significantly lower mutation frequency in the tailless H2A/H3 mutant, indicating a defect in postreplication repair. In summary, our data identify novel roles of the histone H2A and H3 N-tails in (i) regulating the expression of a critical BER enzyme (Mag1), (ii) supporting efficient DNA damage signaling and (iii) facilitating postreplication repair. PMID:25897129

  17. Clipping of Flexible Tails of Histones H3 and H4 Affects the Structure and Dynamics of the Nucleosome

    Science.gov (United States)

    Nurse, Nathan P.; Jimenez-Useche, Isabel; Smith, Ian Tad; Yuan, Chongli

    2013-01-01

    Förster resonance energy transfer was used to monitor the dynamic conformations of mononucleosomes under different chromatin folding conditions to elucidate the role of the flexible N-terminal regions of H3 and H4 histones. The H3 tail was shown to partake in intranucleosomal interactions by restricting the DNA breathing motion and compacting the nucleosome. The H3 tail effects were mostly independent of the ionic strength and valency of the ions. The H4 tail was shown to not greatly affect the nucleosome conformation, but did slightly influence the relative population of the preferred conformation. The role of the H4 tail varied depending on the valency and ionic strength, suggesting that electrostatic forces play a primary role in H4 tail interactions. Interestingly, despite the H4 tail’s lack of influence, when H3 and H4 tails were simultaneously clipped, a more dramatic effect was seen than when only H3 or H4 tails were clipped. The combinatorial effect of H3 and H4 tail truncation suggests a potential mechanism by which various combinations of histone tail modifications can be used to control accessibility of DNA-binding proteins to nucleosomal DNA. PMID:23473491

  18. Automated setup for characterization of intact histone tails in Suz12-/- stem cells

    DEFF Research Database (Denmark)

    Sidoli, Simone; Schwämmle, Veit; Hansen, Thomas Aarup

    Epigenetics is defined as the study of heritable changes that occur without modifying the DNA sequence. Histone proteins are crucial components of epigenetic mechanisms and regulation, since they are fundamental for chromatin structure. Mass spectrometry-based proteomics is already an integrated...

  19. Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription.

    Science.gov (United States)

    Josefowicz, Steven Z; Shimada, Miho; Armache, Anja; Li, Charles H; Miller, Rand M; Lin, Shu; Yang, Aerin; Dill, Brian D; Molina, Henrik; Park, Hee-Sung; Garcia, Benjamin A; Taunton, Jack; Roeder, Robert G; Allis, C David

    2016-10-20

    The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide. Using pharmacological and genetic approaches, we identified mitogen- and stress-activated protein kinases (MSKs) as primary mediators of H3S28ph in macrophages. Cell-free transcription assays demonstrated that H3S28ph directly promotes p300/CBP-dependent transcription. Further, MSKs can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Specific inhibition of MSKs in macrophages selectively reduced transcription of stimulation-induced genes. Our results suggest that MSKs incorporate upstream signaling inputs and control multiple downstream regulators of inducible transcription. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. The amino-terminal tails of histones H2A and H3 coordinate efficient base excision repair, DNA damage signaling and postreplication repair in Saccharomyces cerevisiae.

    Science.gov (United States)

    Meas, Rithy; Smerdon, Michael J; Wyrick, John J

    2015-05-26

    Histone amino-terminal tails (N-tails) are required for cellular resistance to DNA damaging agents; therefore, we examined the role of histone N-tails in regulating DNA damage response pathways in Saccharomyces cerevisiae. Combinatorial deletions reveal that the H2A and H3 N-tails are important for the removal of MMS-induced DNA lesions due to their role in regulating the basal and MMS-induced expression of DNA glycosylase Mag1. Furthermore, overexpression of Mag1 in a mutant lacking the H2A and H3 N-tails rescues base excision repair (BER) activity but not MMS sensitivity. We further show that the H3 N-tail functions in the Rad9/Rad53 DNA damage signaling pathway, but this function does not appear to be the primary cause of MMS sensitivity of the double tailless mutants. Instead, epistasis analyses demonstrate that the tailless H2A/H3 phenotypes are in the RAD18 epistasis group, which regulates postreplication repair. We observed increased levels of ubiquitylated PCNA and significantly lower mutation frequency in the tailless H2A/H3 mutant, indicating a defect in postreplication repair. In summary, our data identify novel roles of the histone H2A and H3 N-tails in (i) regulating the expression of a critical BER enzyme (Mag1), (ii) supporting efficient DNA damage signaling and (iii) facilitating postreplication repair. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. Histone Deacetylase Inhibitors Globally Enhance H3/H4 Tail Acetylation Without Affecting H3 Lysine 56 Acetylation

    OpenAIRE

    Drogaris, Paul; Villeneuve, Val?rie; Pomi?s, Christelle; Lee, Eun-Hye; Bourdeau, V?ronique; Bonneil, ?ric; Ferbeyre, Gerardo; Verreault, Alain; Thibault, Pierre

    2012-01-01

    Histone deacetylase inhibitors (HDACi) represent a promising avenue for cancer therapy. We applied mass spectrometry (MS) to determine the impact of clinically relevant HDACi on global levels of histone acetylation. Intact histone profiling revealed that the HDACi SAHA and MS-275 globally increased histone H3 and H4 acetylation in both normal diploid fibroblasts and transformed human cells. Histone H3 lysine 56 acetylation (H3K56ac) recently elicited much interest and controversy due to its p...

  2. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase

    Science.gov (United States)

    Gatti, Marco; Pinato, Sabrina; Maspero, Elena; Soffientini, Paolo; Polo, Simona; Penengo, Lorenza

    2012-01-01

    Ubiquitination of histones plays a critical role in the regulation of several processes within the nucleus, including maintenance of genome stability and transcriptional regulation. The only known ubiquitination site on histones is represented by a conserved Lys residue located at the C terminus of the protein. Here, we describe a novel ubiquitin mark at the N-terminal tail of histone H2As consisting of two Lys residues at positions 13 and 15 (K13/K15). This “bidentate” site is a target of the DNA damage response (DDR) ubiquitin ligases RNF8 and RNF168. Histone mutants lacking the K13/K15 site impair RNF168- and DNA damage-dependent ubiquitination. Conversely, inactivation of the canonical C-terminal site prevents the constitutive monoubiquitination of histone H2As but does not abolish the ubiquitination induced by RNF168. A ubiquitination-defective mutant is obtained by inactivating both the N- and the C-terminal sites, suggesting that these are unique, non-redundant acceptors of ubiquitination on histone H2As. This unprecedented result implies that RNF168 generates a qualitatively different Ub mark on chromatin. PMID:22713238

  3. Ion Mobility Separation of Variant Histone Tails Extending to the “Middle-down” Range

    Energy Technology Data Exchange (ETDEWEB)

    Shvartsburg, Alexandre A.; Zheng, Yupeng; Smith, Richard D.; Kelleher, Neil

    2012-05-15

    Differential ion mobility spectrometry (FAIMS) can baseline-resolve multiple variants of post-translationally modified peptides extending to the 3 - 4 kDa range, which differ in the localization of a PTM as small as acetylation. Essentially orthogonal separations for different charge states expand the total achievable peak capacity in proportion to the number of observed states that increases for longer polypeptides. This might enable resolving localization variants for even larger peptides and intact proteins.

  4. Field collapse due to band-tail charge in amorphous silicon solar cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qi; Crandall, R.S. [National Renewable Energy Lab., Golden, CO (United States); Schiff, E.A. [Syracuse Univ., NY (United States)

    1996-05-01

    It is common for the fill factor to decrease with increasing illumination intensity in hydrogenated amorphous silicon solar cells. This is especially critical for thicker solar cells, because the decrease is more severe than in thinner cells. Usually, the fill factor under uniformly absorbed red light changes much more than under strongly absorbed blue light. The cause of this is usually assumed to arise from space charge trapped in deep defect states. The authors model this behavior of solar cells using the Analysis of Microelectronic and Photonic Structures (AMPS) simulation program. The simulation shows that the decrease in fill factor is caused by photogenerated space charge trapped in the band-tail states rather than in defects. This charge screens the applied field, reducing the internal field. Owing to its lower drift mobility, the space charge due to holes exceeds that due to electrons and is the main cause of the field screening. The space charge in midgap states is small compared with that in the tails and can be ignored under normal solar-cell operating conditions. Experimentally, the authors measured the photocapacitance as a means to probe the collapsed field. They also explored the light intensity dependence of photocapacitance and explain the decrease of FF with the increasing light intensity.

  5. Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail

    Science.gov (United States)

    Zhang, Yingying; Jurkowska, Renata; Soeroes, Szabolcs; Rajavelu, Arumugam; Dhayalan, Arunkumar; Bock, Ina; Rathert, Philipp; Brandt, Ole; Reinhardt, Richard; Fischle, Wolfgang; Jeltsch, Albert

    2010-01-01

    Using peptide arrays and binding to native histone proteins, we show that the ADD domain of Dnmt3a specifically interacts with the H3 histone 1–19 tail. Binding is disrupted by di- and trimethylation of K4, phosphorylation of T3, S10 or T11 and acetylation of K4. We did not observe binding to the H4 1–19 tail. The ADD domain of Dnmt3b shows the same binding specificity, suggesting that the distinct biological functions of both enzymes are not related to their ADD domains. To establish a functional role of the ADD domain binding to unmodified H3 tails, we analyzed the DNA methylation of in vitro reconstituted chromatin with Dnmt3a2, the Dnmt3a2/Dnmt3L complex, and the catalytic domain of Dnmt3a. All Dnmt3a complexes preferentially methylated linker DNA regions. Chromatin substrates with unmodified H3 tail or with H3K9me3 modification were methylated more efficiently by full-length Dnmt3a and full-length Dnmt3a/3L complexes than chromatin trimethylated at H3K4. In contrast, the catalytic domain of Dnmt3a was not affected by the H3K4me3 modification. These results demonstrate that the binding of the ADD domain to H3 tails unmethylated at K4 leads to the preferential methylation of DNA bound to chromatin with this modification state. Our in vitro results recapitulate DNA methylation patterns observed in genome-wide DNA methylation studies. PMID:20223770

  6. A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 Lys-9 demarcates distinct regions of silent chromatin.

    Science.gov (United States)

    Sims, Jennifer K; Houston, Sabrina I; Magazinnik, Tanya; Rice, Judd C

    2006-05-05

    The specific post-translational modifications of the histone proteins are associated with specific DNA-templated processes, such as transcriptional activation or repression. To investigate the biological role(s) of histone H4 lysine 20 (H4 Lys-20) methylation, we created a novel panel of antibodies that specifically detected mono-, di-, or trimethylated H4 Lys-20. We report that the different methylated forms of H4 Lys-20 are compartmentalized within visually distinct, transcriptionally silent regions in the mammalian nucleus. Interestingly, direct comparison of methylated H4 Lys-20 with the different methylated states of histone H3 lysine 9 (H3 Lys-9) revealed significant overlap and exclusion between the specific groups of methyl modifications. Trimethylated H4 Lys-20 and H3 Lys-9 were both selectively enriched within pericentric heterochromatin. Similarly, monomethylated H4 Lys-20 and H3 Lys-9 partitioned together and the dimethylated forms partitioned together within the chromosome arms; however, the mono- and dimethylated modifications were virtually exclusive. These findings strongly suggest that the combinatorial presence or absence of the different methylated states of H4 Lys-20 and H3 Lys-9 define particular types of silent chromatin. Consistent with this, detailed analysis of monomethylated H4 Lys-20 and H3 Lys-9 revealed that both were preferentially and selectively enriched within the same nucleosome particle in vivo. Collectively, these findings define a novel trans-tail histone code involving monomethylated H4 Lys-20 and H3 Lys-9 that act cooperatively to mark distinct regions of silent chromatin within the mammalian epigenome.

  7. Middle-Down and Chemical Proteomic Approaches to Reveal Histone H4 Modification Dynamics in Cell Cycle: Label-Free Semi-Quantification of Histone Tail Peptide Modifications Including Phosphorylation and Highly Sensitive Capture of Histone PTM Binding Proteins Using Photo-Reactive Crosslinkers.

    Science.gov (United States)

    Yamamoto, Kazuki; Chikaoka, Yoko; Hayashi, Gosuke; Sakamoto, Ryosuke; Yamamoto, Ryuji; Sugiyama, Akira; Kodama, Tatsuhiko; Okamoto, Akimitsu; Kawamura, Takeshi

    2015-01-01

    Mass spectrometric proteomics is an effective approach for identifying and quantifying histone post-translational modifications (PTMs) and their binding proteins, especially in the cases of methylation and acetylation. However, another vital PTM, phosphorylation, tends to be poorly quantified because it is easily lost and inefficiently ionized. In addition, PTM binding proteins for phosphorylation are sometimes resistant to identification because of their variable binding affinities. Here, we present our efforts to improve the sensitivity of detection of histone H4 tail peptide phosphorylated at serine 1 (H4S1ph) and our successful identification of an H4S1ph binder candidate by means of a chemical proteomics approach. Our nanoLC-MS/MS system permitted semi-quantitative label-free analysis of histone H4 PTM dynamics of cell cycle-synchronized HeLa S3 cells, including phosphorylation, methylation, and acetylation. We show that H4S1ph abundance on nascent histone H4 unmethylated at lysine 20 (H4K20me0) peaks from late S-phase to M-phase. We also attempted to characterize effects of phosphorylation at H4S1 on protein-protein interactions. Specially synthesized photoaffinity bait peptides specifically captured 14-3-3 proteins as novel H4S1ph binding partners, whose interaction was otherwise undetectable by conventional peptide pull-down experiments. This is the first report that analyzes dynamics of PTM pattern on the whole histone H4 tail during cell cycle and enables the identification of PTM binders with low affinities using high-resolution mass spectrometry and photo-affinity bait peptides.

  8. Precision mapping of coexisting modifications in histone H3 tails from embryonic stem cells by ETD-MS/MS

    DEFF Research Database (Denmark)

    Jung, Hye Ryung; Sidoli, Simone; Haldbo, Simon

    2013-01-01

    H3 N-terminal tail peptides (amino acids 1-50, 5-6 kDa) were separated by optimized weak cation exchange/hydrophilic interaction liquid chromatography (WCX/HILIC) and sequenced online by electron transfer dissociation (ETD) tandem mass spectrometry (MS/MS). High mass accuracy and near complete...

  9. A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding.

    Science.gov (United States)

    Kostrhon, Sebastian; Kontaxis, Georg; Kaufmann, Tanja; Schirghuber, Erika; Kubicek, Stefan; Konrat, Robert; Slade, Dea

    2017-10-27

    N-terminal histone tails are subject to many posttranslational modifications that are recognized by and interact with designated reader domains in histone-binding proteins. BROMO domain adjacent to zinc finger 2B (BAZ2B) is a multidomain histone-binding protein that contains two histone reader modules, a plant homeodomain (PHD) and a bromodomain (BRD), linked by a largely disordered linker. Although previous studies have reported specificity of the PHD domain for the unmodified N terminus of histone H3 and of the BRD domain for H3 acetylated at Lys14 (H3K14ac), the exact mode of H3 binding by BAZ2B and its regulation are underexplored. Here, using isothermal titration calorimetry and NMR spectroscopy, we report that acidic residues in the BAZ2B PHD domain are essential for H3 binding and that BAZ2B PHD-BRD establishes a polyvalent interaction with H3K14ac. Furthermore, we provide evidence that the disordered interdomain linker modulates the histone-binding affinity by interacting with the PHD domain. In particular, lysine-rich stretches in the linker, which resemble the positively charged N terminus of histone H3, reduce the binding affinity of the PHD finger toward the histone substrate. Phosphorylation, acetylation, or poly(ADP-ribosyl)ation of the linker residues may therefore act as a cellular mechanism to transiently tune BAZ2B histone-binding affinity. Our findings further support the concept of interdomain linkers serving a dual role in substrate binding by appropriately positioning the adjacent domains and by electrostatically modulating substrate binding. Moreover, inhibition of histone binding by a histone-mimicking interdomain linker represents another example of regulation of protein-protein interactions by intramolecular mimicry. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Large scale analysis of co-existing post-translational modifications in histone tails reveals global fine structure of cross-talk

    DEFF Research Database (Denmark)

    Schwämmle, Veit; Aspalter, Claudia-Maria; Sidoli, Simone

    2014-01-01

    Mass spectrometry (MS) is a powerful analytical method for the identification and quantification of co-existing post-translational modifications in histone proteins. One of the most important challenges in current chromatin biology is to characterize the relationships between co-existing histone ...

  11. The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tail 'histone code' and Riz1 tumor suppressor function.

    Science.gov (United States)

    Congdon, Lauren M; Sims, Jennifer K; Tuzon, Creighton T; Rice, Judd C

    2014-04-01

    PR-Set7/Set8/KMT5a is the sole histone H4 lysine 20 monomethyltransferase (H4K20me1) in metazoans and is essential for proper cell division and genomic stability. We unexpectedly discovered that normal cellular levels of monomethylated histone H3 lysine 9 (H3K9me1) were also dependent on PR-Set7, but independent of its catalytic activity. This observation suggested that PR-Set7 interacts with an H3K9 monomethyltransferase to establish the previously reported H4K20me1-H3K9me1 trans-tail 'histone code'. Here we show that PR-Set7 specifically and directly binds the C-terminus of the Riz1/PRDM2/KMT8 tumor suppressor and demonstrate that the N-terminal PR/SET domain of Riz1 preferentially monomethylates H3K9. The PR-Set7 binding domain was required for Riz1 nuclear localization and maintenance of the H4K20me1-H3K9me1 trans-tail 'histone code'. Although Riz1 can function as a repressor, Riz1/H3K9me1 was dispensable for the repression of genes regulated by PR-Set7/H4K20me1. Frameshift mutations resulting in a truncated Riz1 incapable of binding PR-Set7 occur frequently in various aggressive cancers. In these cancer cells, expression of wild-type Riz1 restored tumor suppression by decreasing proliferation and increasing apoptosis. These phenotypes were not observed in cells expressing either the Riz1 PR/SET domain or PR-Set7 binding domain indicating that Riz1 methyltransferase activity and PR-Set7 binding domain are both essential for Riz1 tumor suppressor function.

  12. The effects of localized tail states on charge transport mechanisms in amorphous zinc tin oxide Schottky diodes

    Science.gov (United States)

    Son, Youngbae; Peterson, Rebecca L.

    2017-12-01

    Temperature-dependent current–voltage measurements were performed on vertical Schottky diodes made with solution-processed amorphous zinc tin oxide (a-ZTO) semiconductor and palladium rectifying contacts. Above 260 K, forward bias electron transport occurs via thermionic emission over an inhomogeneous, voltage-dependent Schottky barrier with {\\bar{φ }}b0 = 0.72 eV, σ 0 = 0.12 eV, and A* = 44 A cm‑2 K‑2, where {\\bar{φ }}b0 and {σ }0 are the mean potential barrier and its standard deviation at zero bias, respectively, and A* is Richardson’s constant. For large currents, the series ohmic resistance of the bulk semiconductor dominates. At temperatures below 260 K, less carriers are excited from localized states below the conduction band edge, and space-charge-limited current (SCLC) dominates. The exponential tail density of states parameters extracted for a-ZTO are g tc = 1.34 × 1019 cm‑3 eV‑1 and kT t = 26 meV. The intermediate tail state density in a-ZTO, less than that of amorphous silicon and greater than that of amorphous indium gallium zinc oxide, allows for experimental observation of a temperature-dependent transition of bulk charge transport mechanisms in strong forward bias from semiconductor-like ohmic conduction near room temperature to insulator-like SCLC at lower temperatures. In reverse bias, the same tail states lead to modified Poole–Frenkel emission, reducing the leakage current. The frequency response of a half-wave rectifier and diode impedance spectroscopy confirm that the Schottky diode cut-off frequency is above 1 MHz.

  13. Intricate Effects of α-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4.

    Science.gov (United States)

    Fulton, Melody D; Zhang, Jing; He, Maomao; Ho, Meng-Chiao; Zheng, Y George

    2017-07-18

    Chemical modifications of the DNA and nucleosomal histones tightly control the gene transcription program in eukaryotic cells. The "histone code" hypothesis proposes that the frequency, combination, and location of post-translational modifications (PTMs) of the core histones compose a complex network of epigenetic regulation. Currently, there are at least 23 different types and >450 histone PTMs that have been discovered, and the PTMs of lysine and arginine residues account for a crucial part of the histone code. Although significant progress has been achieved in recent years, the molecular basis for the histone code is far from being fully understood. In this study, we investigated how naturally occurring N-terminal acetylation and PTMs of histone H4 lysine-5 (H4K5) affect arginine-3 methylation catalyzed by both type I and type II PRMTs at the biochemical level. Our studies found that acylations of H4K5 resulted in decreased levels of arginine methylation by PRMT1, PRMT3, and PRMT8. In contrast, PRMT5 exhibits an increased rate of arginine methylation upon H4K5 acetylation, propionylation, and crotonylation, but not upon H4K5 methylation, butyrylation, or 2-hydroxyisobutyrylation. Methylation of H4K5 did not affect arginine methylation by PRMT1 or PRMT5. There was a small increase in the rate of arginine methylation by PRMT8. Strikingly, a marked increase in the rate of arginine methylation was observed for PRMT3. Finally, N-terminal acetylation reduced the rate of arginine methylation by PRMT3 but had little influence on PRMT1, -5, and -8 activity. These results together highlight the underlying mechanistic differences in substrate recognition among different PRMTs and pave the way for the elucidation of the complex interplay of histone modifications.

  14. Site-specific quantification of lysine acetylation in the N-terminal tail of histone H4 using a double-labelling, targeted UHPLC MS/MS approach

    NARCIS (Netherlands)

    D'Urzo, Annalisa; Boichenko, Alexander P.; van den Bosch, Thea; Hermans, Jos; Dekker, Frank; Andrisano, Vincenza; Bischoff, Rainer

    We developed a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the site-specific quantification of lysine acetylation in the N-terminal region of histone H4 by combining chemical derivatization at the protein and peptide levels with digestion using chymotrypsin and

  15. Fast, single-step, and surfactant-free oligonucleotide modification of gold nanoparticles using DNA with a positively charged tail

    NARCIS (Netherlands)

    Gill, Ron; Göeken, Kristian; Subramaniam, Vinod

    2013-01-01

    Fast modification of large gold nanoparticles with DNA is achieved by using DNA with a polycationic tail. The conjugated DNA is available for specific hybridization, and therefore can be used for DNA-based assays or for constructing nanoparticle superstructures based on DNA hybridization

  16. Fast, single-step, and surfactant-free oligonucleotide modification of gold nanoparticles using DNA with a positively charged tail

    NARCIS (Netherlands)

    Gill, R.; Goeken, K.; Subramaniam, V.

    2013-01-01

    Fast modification of large gold nanoparticles with DNA is achieved by using DNA with a polycationic tail. The conjugated DNA is available for specific hybridization, and therefore can be used for DNA-based assays or for constructing nanoparticle superstructures based on DNA hybridization.

  17. Histone code or not? Combinatorial pattern analyses of histone modifications

    Science.gov (United States)

    Zang, Chongzhi; Peng, Weiqun; Wang, Zhibin; Schones, Dustin E.; Barski, Artem; Cuddapah, Suresh; Cui, Kairong; Roh, Tae-Young; Zhao, Keji; Rosenfeld, Jeffrey; Zhang, Michael

    2008-03-01

    Eukaryotic genomes are organized into chromatin, the structure of which plays critical role in the program of gene expression. Chromatin structure and function is regulated by a myriad of posttranslational modifications on histone tails of the nucleosomes, the fundamental unit of chromatin. It remains unclear how different modifications interact. Based on high- resolution genomic maps of close to 40 histone methylations and acetylations in human T-cells obtained experimentally by ChIP- Seq technique, we investigated the combinatorial patterns of histone modifications at gene promoter regions. We found that a very limited number of patterns dominate. Modifications within a pattern are strongly correlated and each pattern is associated with a distinct gene expression distribution. Our results suggest that it is the patterns rather than the individual modifications that affect the downstream readout.

  18. The C Terminus of the Histone Chaperone Asf1 Cross-Links to Histone H3 in Yeast and Promotes Interaction with Histones H3 and H4

    OpenAIRE

    Dennehey, Briana K; Noone, Seth; Liu, Wallace H.; Smith, Luke; Churchill, Mair E. A.; Tyler, Jessica K.

    2013-01-01

    The central histone H3/H4 chaperone Asf1 comprises a highly conserved globular core and a divergent C-terminal tail. While the function and structure of the Asf1 core are well known, the function of the tail is less well understood. Here, we have explored the role of the yeast (yAsf1) and human (hAsf1a and hAsf1b) Asf1 tails in Saccharomyces cerevisiae. We show, using a photoreactive, unnatural amino acid, that Asf1 tail residue 210 cross-links to histone H3 in vivo and, furthe...

  19. Object Picture, Quasinormal Modes and Late Time Tails of Fermion Perturbations in Stringy Black Holes with U(1) Charges

    Science.gov (United States)

    Piedra, Owen Pavel Fernández; Nuñez, Fidel Sosa; Castillo, Jose Bernal; Santana, Yulier Jimenez

    The aim of the present report is the study of massless fermion perturbations outside five-dimensional stringy black holes with U(1) charges. The Dirac equation was numerically solved to obtain the time profiles for evolving fermion fields, and the quasinormal frequencies at intermediate times are computed by numerical Prony fitting and semi-analytical Wentzel-Kramers-Brillouin (WKB) expansion at sixth-order. We also computed numerically the latetime power law decay factors, showing that there are in correspondence with previously reported results for the case of boson fields in higher-dimensional odd spacetimes. The dependence of quasinormal frequencies with U(1) compactification charges are studied.

  20. Object picture, quasinormal modes and late time tails of fermion perturbations in stringy black hole with U(1) charges

    OpenAIRE

    Piedra, Owen Pavel Fernández; Sosa, Fidel; Bernal-Castillo, José L.; Jimenez, Yulier

    2011-01-01

    The aim of the present report is to study massless fermion perturbations outside five-dimensional stringy black holes with U(1) charges. The Dirac equation was numerically solved to obtain the time profiles for the evolving fermion fields, and the quasinormal frequencies at intermediate times are computed by numerical Prony fitting and semianalytical WKB expansion at sixth order. We also computed numerically the late-time power law decay factors, showing that there are in correspondence with ...

  1. Histone H3 Lysine Methylation in Cognition and Intellectual Disability Disorders

    Science.gov (United States)

    Parkel, Sven; Lopez-Atalaya, Jose P.; Barco, Angel

    2013-01-01

    Recent research indicates that epigenetic mechanisms and, in particular, the post-translational modification (PTM) of histones may contribute to memory encoding and storage. Among the dozens of possible histone PTMs, the methylation/demethylation of lysines in the N-terminal tail of histone H3 exhibits particularly strong links with cognitive…

  2. Biochemical Analysis Reveals the Multifactorial Mechanism of Histone H3 Clipping by Chicken Liver Histone H3 Protease

    KAUST Repository

    Chauhan, Sakshi

    2016-09-02

    Proteolytic clipping of histone H3 has been identified in many organisms. Despite several studies, the mechanism of clipping, the substrate specificity, and the significance of this poorly understood epigenetic mechanism are not clear. We have previously reported histone H3 specific proteolytic clipping and a protein inhibitor in chicken liver. However, the sites of clipping are still not known very well. In this study, we attempt to identify clipping sites in histone H3 and to determine the mechanism of inhibition by stefin B protein, a cysteine protease inhibitor. By employing site-directed mutagenesis and in vitro biochemical assays, we have identified three distinct clipping sites in recombinant human histone H3 and its variants (H3.1, H3.3, and H3t). However, post-translationally modified histones isolated from chicken liver and Saccharomyces cerevisiae wild-type cells showed different clipping patterns. Clipping of histone H3 N-terminal tail at three sites occurs in a sequential manner. We have further observed that clipping sites are regulated by the structure of the N-terminal tail as well as the globular domain of histone H3. We also have identified the QVVAG region of stefin B protein to be very crucial for inhibition of the protease activity. Altogether, our comprehensive biochemical studies have revealed three distinct clipping sites in histone H3 and their regulation by the structure of histone H3, histone modifications marks, and stefin B.

  3. The emerging functions of histone demethylases

    DEFF Research Database (Denmark)

    Agger, Karl; Christensen, Jesper; Cloos, Paul Ac

    2008-01-01

    Epigenetic information refers to heritable changes in gene function that are stable between cell divisions but which is not a result of changes in the DNA sequence. Part of the epigenetic mechanism has been ascribed to modifications of histones or DNA that affects the transcription of specific...... genes. In this context, post-translational modifications of histone tails, in particular methylation of lysines, are regarded as important for the storage of epigenetic information. Regulation of this information plays an important role during cellular differentiation where cells with different....... The recent identification of proteins with histone demethylase activity has shown that the methylated mark is much more dynamic than previously anticipated, thereby potentially challenging the concept of histone-methylation in stable epigenetic programming....

  4. ADP-ribosylation of histones by ARTD1: an additional module of the histone code?

    Science.gov (United States)

    Hottiger, Michael O

    2011-06-06

    ADP-ribosylation is a covalent post-translational protein modification catalyzed by ADP-ribosyltransferases and is involved in important processes such as cell cycle regulation, DNA damage response, replication or transcription. Histones are ADP-ribosylated by ADP-ribosyltransferase diphtheria toxin-like 1 at specific amino acid residues, in particular lysines, of the histones tails. Specific ADP-ribosyl hydrolases and poly-ADP-ribose glucohydrolases degrade the ADP-ribose polymers. The ADP-ribose modification is read by zinc finger motifs or macrodomains, which then regulate chromatin structure and transcription. Thus, histone ADP-ribosylation may be considered an additional component of the histone code. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  5. Electrodialytic remediation of suspended mine tailings

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Rojo, Adrian; Pino, Denisse

    2008-01-01

    experiment at 40 mA, with approximately 137.5 g mine tailings on dry basis. The removal for a static (baseline) experiment only amounted 15% when passing approximately the same amount of charge through 130 g of mine tailings. The use of air bubbling to keep the tailings suspended increased the removal...

  6. Molecular mechanisms for the regulation of histone mRNA stem-loop-binding protein by phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jun; Tan, Dazhi; DeRose, Eugene F.; Perera, Lalith; Dominski, Zbigniew; Marzluff, William F.; Tong, Liang; Tanaka Hall, Traci M. [NIH; (UNC); (Columbia)

    2014-08-06

    Replication-dependent histone mRNAs end with a conserved stem loop that is recognized by stem-loop–binding protein (SLBP). The minimal RNA-processing domain of SLBP is phosphorylated at an internal threonine, and Drosophila SLBP (dSLBP) also is phosphorylated at four serines in its 18-aa C-terminal tail. We show that phosphorylation of dSLBP increases RNA-binding affinity dramatically, and we use structural and biophysical analyses of dSLBP and a crystal structure of human SLBP phosphorylated on the internal threonine to understand the striking improvement in RNA binding. Together these results suggest that, although the C-terminal tail of dSLBP does not contact the RNA, phosphorylation of the tail promotes SLBP conformations competent for RNA binding and thereby appears to reduce the entropic penalty for the association. Increased negative charge in this C-terminal tail balances positively charged residues, allowing a more compact ensemble of structures in the absence of RNA.

  7. Detection of histone modifications in plant leaves.

    Science.gov (United States)

    Jaskiewicz, Michal; Peterhansel, Christoph; Conrath, Uwe

    2011-09-23

    Chromatin structure is important for the regulation of gene expression in eukaryotes. In this process, chromatin remodeling, DNA methylation, and covalent modifications on the amino-terminal tails of histones H3 and H4 play essential roles(1-2). H3 and H4 histone modifications include methylation of lysine and arginine, acetylation of lysine, and phosphorylation of serine residues(1-2). These modifications are associated either with gene activation, repression, or a primed state of gene that supports more rapid and robust activation of expression after perception of appropriate signals (microbe-associated molecular patterns, light, hormones, etc.)(3-7). Here, we present a method for the reliable and sensitive detection of specific chromatin modifications on selected plant genes. The technique is based on the crosslinking of (modified) histones and DNA with formaldehyde(8,9), extraction and sonication of chromatin, chromatin immunoprecipitation (ChIP) with modification-specific antibodies(9,10), de-crosslinking of histone-DNA complexes, and gene-specific real-time quantitative PCR. The approach has proven useful for detecting specific histone modifications associated with C(4;) photosynthesis in maize(5,11) and systemic immunity in Arabidopsis(3).

  8. Toward breaking the histone code: bayesian graphical models for histone modifications.

    Science.gov (United States)

    Mitra, Riten; Müller, Peter; Liang, Shoudan; Xu, Yanxun; Ji, Yuan

    2013-08-01

    Histones are proteins that wrap DNA around in small spherical structures called nucleosomes. Histone modifications (HMs) refer to the post-translational modifications to the histone tails. At a particular genomic locus, each of these HMs can either be present or absent, and the combinatory patterns of the presence or absence of multiple HMs, or the histone codes, are believed to coregulate important biological processes. We aim to use raw data on HM markers at different genomic loci to (1) decode the complex biological network of HMs in a single region, and (2) demonstrate how the HM networks differ in different regulatory regions. We suggest that these differences in network attributes form a significant link between histones and genomic functions. We develop a powerful graphical model under the Bayesian paradigm. Posterior inference is fully probabilistic, allowing us to compute the probabilities of distinct dependence patterns of the HMs using graphs. Furthermore, our model-based framework allows for easy but important extensions for inference on differential networks under various conditions, such as the different annotations of the genomic locations (eg, promoters versus insulators). We applied these models to ChIP-Seq data based on CD4+ T lymphocytes. The results confirmed many existing findings and provided a unified tool to generate various promising hypotheses. Differential network analyses revealed new insights on coregulation of HMs of transcriptional activities in different genomic regions. The use of Bayesian graphical models and borrowing strength across different conditions provide high power to infer histone networks and their differences.

  9. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3

    DEFF Research Database (Denmark)

    Cloos, Paul A C; Christensen, Jesper; Agger, Karl

    2006-01-01

    Methylation of lysine and arginine residues on histone tails affects chromatin structure and gene transcription. Tri- and dimethylation of lysine 9 on histone H3 (H3K9me3/me2) is required for the binding of the repressive protein HP1 and is associated with heterochromatin formation and transcript...

  10. Histone Acetylation near the Nucleosome Dyad Axis Enhances Nucleosome Disassembly by RSC and SWI/SNF.

    Science.gov (United States)

    Chatterjee, Nilanjana; North, Justin A; Dechassa, Mekonnen Lemma; Manohar, Mridula; Prasad, Rashmi; Luger, Karolin; Ottesen, Jennifer J; Poirier, Michael G; Bartholomew, Blaine

    2015-12-01

    Signaling associated with transcription activation occurs through posttranslational modification of histones and is best exemplified by lysine acetylation. Lysines are acetylated in histone tails and the core domain/lateral surface of histone octamers. While acetylated lysines in histone tails are frequently recognized by other factors referred to as "readers," which promote transcription, the mechanistic role of the modifications in the lateral surface of the histone octamer remains unclear. By using X-ray crystallography, we found that acetylated lysines 115 and 122 in histone H3 are solvent accessible, but in biochemical assays they appear not to interact with the bromodomains of SWI/SNF and RSC to enhance recruitment or nucleosome mobilization, as previously shown for acetylated lysines in H3 histone tails. Instead, we found that acetylation of lysines 115 and 122 increases the predisposition of nucleosomes for disassembly by SWI/SNF and RSC up to 7-fold, independent of bromodomains, and only in conjunction with contiguous nucleosomes. Thus, in combination with SWI/SNF and RSC, acetylation of lateral surface lysines in the histone octamer serves as a crucial regulator of nucleosomal dynamics distinct from the histone code readers and writers. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  11. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

  12. Top-down and Middle-down Protein Analysis Reveals that Intact and Clipped Human Histones Differ in Post-translational Modification Patterns

    DEFF Research Database (Denmark)

    Tvardovskiy, Andrey; Wrzesinski, Krzysztof; Sidoli, Simone

    2015-01-01

    . Using top-down and middle-down protein analysis by mass spectrometry, we report histone H2B and H3 N-terminal tail clipping in human hepatocytes and demonstrate a relationship between clipping and coexisting PTMs of histone H3. Histones H2B and H3 undergo proteolytic processing in primary human...

  13. File list: His.Oth.05.AllAg.Tail_fibroblast [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Oth.05.AllAg.Tail_fibroblast mm9 Histone Others Tail fibroblast SRX335673,SRX33...5668,SRX335667,SRX335674,SRX335665 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Oth.05.AllAg.Tail_fibroblast.bed ...

  14. File list: His.Oth.10.AllAg.Tail_fibroblast [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Oth.10.AllAg.Tail_fibroblast mm9 Histone Others Tail fibroblast SRX335673,SRX33...5668,SRX335667,SRX335674,SRX335665 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Oth.10.AllAg.Tail_fibroblast.bed ...

  15. Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.

    Directory of Open Access Journals (Sweden)

    Shrividhya Srinivasan

    2008-10-01

    Full Text Available Polycomb and trithorax group proteins regulate cellular pluripotency and differentiation by maintaining hereditable states of transcription. Many Polycomb and trithorax group proteins have been implicated in the covalent modification or remodeling of chromatin, but how they interact with each other and the general transcription machinery to regulate transcription is not well understood. The trithorax group protein Kismet-L (KIS-L is a member of the CHD subfamily of chromatin-remodeling factors that plays a global role in transcription by RNA polymerase II (Pol II. Mutations in CHD7, the human counterpart of kis, are associated with CHARGE syndrome, a developmental disorder affecting multiple tissues and organs. To clarify how KIS-L activates gene expression and counteracts Polycomb group silencing, we characterized defects resulting from the loss of KIS-L function in Drosophila. These studies revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate elongation by Pol II. The presence of two chromodomains in KIS-L suggested that its recruitment or function might be regulated by the methylation of histone H3 lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed significant overlap between the distributions of KIS-L, ASH1, and TRX on polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and loss of TRX or ASH1 function did not alter the association of KIS-L with chromatin. By contrast, loss of kis function led to a dramatic reduction in the levels of TRX and ASH1 associated with chromatin and was accompanied by increased histone H3 lysine 27 methylation-a modification required for Polycomb group repression. A similar increase in H3 lysine 27 methylation was observed in ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early elongation and counteracts Polycomb group repression by recruiting the ASH1 and TRX histone methyltransferases to chromatin.

  16. SnapShot: histone modifications

    National Research Council Canada - National Science Library

    Huang, He; Sabari, Benjamin R; Garcia, Benjamin A; Allis, C David; Zhao, Yingming

    2014-01-01

    Histone proteins are decorated by a variety of protein posttranslational modifications called histone marks that modulate chromatin structure and function, contributing to the cellular gene expression program...

  17. Inhibition of histone binding by supramolecular hosts

    Science.gov (United States)

    Allen, Hillary F.; Daze, Kevin D.; Shimbo, Takashi; Lai, Anne; Musselman, Catherine A.; Sims, Jennifer K.; Wade, Paul A.; Hof†, Fraser; Kutateladze, Tatiana G.

    2015-01-01

    The tandem PHD (plant homeodomain) fingers of the CHD4 (chromodomain helicase DNA-binding protein 4) ATPase are epigenetic readers that bind either unmodified histone H3 tails or H3K9me3 (histone H3 trimethylated at Lys9). This dual function is necessary for the transcriptional and chromatin remodelling activities of the NuRD (nucleosome remodelling and deacetylase) complex. In the present paper, we show that calixarene-based supramolecular hosts disrupt binding of the CHD4 PHD2 finger to H3K9me3, but do not affect the interaction of this protein with the H3K9me0 (unmodified histone H3) tail. A similar inhibitory effect, observed for the association of chromodomain of HP1γ (heterochromatin protein 1γ) with H3K9me3, points to a general mechanism of methyl-lysine caging by calixarenes and suggests a high potential for these compounds in biochemical applications. Immunofluorescence analysis reveals that the supramolecular agents induce changes in chromatin organization that are consistent with their binding to and disruption of H3K9me3 sites in living cells. The results of the present study suggest that the aromatic macrocyclic hosts can be used as a powerful new tool for characterizing methylation-driven epigenetic mechanisms. PMID:24576085

  18. Telomeres, histone code, and DNA damage response.

    Science.gov (United States)

    Misri, S; Pandita, S; Kumar, R; Pandita, T K

    2008-01-01

    Genomic stability is maintained by telomeres, the end terminal structures that protect chromosomes from fusion or degradation. Shortening or loss of telomeric repeats or altered telomere chromatin structure is correlated with telomere dysfunction such as chromosome end-to-end associations that could lead to genomic instability and gene amplification. The structure at the end of telomeres is such that its DNA differs from DNA double strand breaks (DSBs) to avoid nonhomologous end-joining (NHEJ), which is accomplished by forming a unique higher order nucleoprotein structure. Telomeres are attached to the nuclear matrix and have a unique chromatin structure. Whether this special structure is maintained by specific chromatin changes is yet to be thoroughly investigated. Chromatin modifications implicated in transcriptional regulation are thought to be the result of a code on the histone proteins (histone code). This code, involving phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones, is believed to regulate chromatin accessibility either by disrupting chromatin contacts or by recruiting non-histone proteins to chromatin. The histone code in which distinct histone tail-protein interactions promote engagement may be the deciding factor for choosing specific DSB repair pathways. Recent evidence suggests that such mechanisms are involved in DNA damage detection and repair. Altered telomere chromatin structure has been linked to defective DNA damage response (DDR), and eukaryotic cells have evolved DDR mechanisms utilizing proficient DNA repair and cell cycle checkpoints in order to maintain genomic stability. Recent studies suggest that chromatin modifying factors play a critical role in the maintenance of genomic stability. This review will summarize the role of DNA damage repair proteins specifically ataxia-telangiectasia mutated (ATM) and its effectors and the telomere complex in maintaining genome stability. Copyright 2008 S. Karger

  19. Physicochemical modifications of histones and their impact on epigenomics.

    Science.gov (United States)

    Andreoli, Federico; Del Rio, Alberto

    2014-09-01

    The study of histone post-translational modifications (PTMs) has made extraordinary progress over the past few years and many epigenetic modifications have been identified and found to be associated with fundamental biological processes and pathological conditions. Most histone-modifying enzymes produce specific covalent modifications on histone tails that, taken together, elicit complex and concerted processes. An even higher level of complexity is generated by the action of small molecules that are able to modulate pharmacologically epigenetic enzymes and interfere with these biochemical mechanisms. In this article, we provide an overview of histone PTMs by reviewing and discussing them in terms of their physicochemical properties, emphasizing these concepts in view of recent research efforts to elucidate epigenetic mechanisms and devise future epigenetic drugs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. A subset of replication-dependent histone mRNAs are expressed as polyadenylated RNAs in terminally differentiated tissues

    OpenAIRE

    Lyons, Shawn M.; Cunningham, Clark H.; Welch, Joshua D; Groh, Beezly; Guo, Andrew Y.; Wei, Bruce; Whitfield, Michael L.; Xiong, Yue; Marzluff, William F.

    2016-01-01

    Histone proteins are synthesized in large amounts during S-phase to package the newly replicated DNA, and are among the most stable proteins in the cell. The replication-dependent (RD)-histone mRNAs expressed during S-phase end in a conserved stem-loop rather than a polyA tail. In addition, there are replication-independent (RI)-histone genes that encode histone variants as polyadenylated mRNAs. Most variants have specific functions in chromatin, but H3.3 also serves as a replacement histone ...

  1. Epigenetic therapy of cancer with histone deacetylase inhibitors

    Directory of Open Access Journals (Sweden)

    K C Lakshmaiah

    2014-01-01

    Full Text Available Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT and Histone Deacetylase (HDAC control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8, Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10, Class III HDAC and Class IV (HDAC11. Histone Deacetylase Inhibitors (HDACI exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates. The effects of HDACI on gene transcription are complex. They cause cell cycle arrest, inhibit DNA repair, induce apoptosis and acetylate non histone proteins causing downstream alterations in gene expression. HDACI are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two. They are classified into four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides. This review describes the clinical utility of HDACI as monotherapy as well as combination therapy with other treatment modalities such as chemotherapy and radiotherapy. Adverse effects and shortcomings of treatment with HDACI are also discussed in detail.

  2. Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.

    Science.gov (United States)

    Brest, Patrick; Gustafsson, Mattias; Mossberg, Ann-Kristin; Gustafsson, Lotta; Duringer, Caroline; Hamiche, Ali; Svanborg, Catharina

    2007-12-01

    Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.

  3. Dynamic changes of histone H3 marks during Caenorhabditis elegans lifecycle revealed by middle-down proteomics

    DEFF Research Database (Denmark)

    Sidoli, Simone; Vandamme, Julien; Elisabetta Salcini, Anna

    2016-01-01

    that is transmitted during dauer formation. Collectively, our data describe the dynamics of histone H3 combinatorial code during C. elegans lifecycle and demonstrate the feasibility of using middle-down proteomics to study in vivo development of multicellular organisms. This article is protected by copyright. All......We applied a middle-down proteomics strategy for large scale protein analysis during in vivo development of Caenorhabditis elegans. We characterized post-translational modifications (PTMs) on histone H3 N-terminal tails at eight time points during the C. elegans lifecycle, including embryo, larval...... stages (L1 to L4), dauer and L1/L4 post dauer. Histones were analyzed by our optimized middle-down protein sequencing platform using high mass accuracy tandem mass spectrometry. This allows quantification of intact histone tails and detailed characterization of distinct histone tails carrying co...

  4. Synthetic histone code.

    Science.gov (United States)

    Fischle, Wolfgang; Mootz, Henning D; Schwarzer, Dirk

    2015-10-01

    Chromatin is the universal template of genetic information in all eukaryotic cells. This complex of DNA and histone proteins not only packages and organizes genomes but also regulates gene expression. A multitude of posttranslational histone modifications and their combinations are thought to constitute a code for directing distinct structural and functional states of chromatin. Methods of protein chemistry, including protein semisynthesis, amber suppression technology, and cysteine bioconjugation, have enabled the generation of so-called designer chromatin containing histones in defined and homogeneous modification states. Several of these approaches have matured from proof-of-concept studies into efficient tools and technologies for studying the biochemistry of chromatin regulation and for interrogating the histone code. We summarize pioneering experiments and recent developments in this exciting field of chemical biology. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Global histone analysis by mass spectrometry reveals a high content of acetylated lysine residues in the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Trelle, Morten Beck; Salcedo-Amaya, Adriana M; Cohen, Adrian

    2009-01-01

    Post-translational modifications (PTMs) of histone tails play a key role in epigenetic regulation of gene expression in a range of organisms from yeast to human, however, little is known about histone proteins from the parasite that causes malaria in humans, Plasmodium falciparum. We characterized...

  6. Developmentally Regulated Post-translational Modification of Nucleoplasmin Controls Histone Sequestration and Deposition

    Directory of Open Access Journals (Sweden)

    Takashi Onikubo

    2015-03-01

    Full Text Available Nucleoplasmin (Npm is an abundant histone chaperone in vertebrate oocytes and embryos. During embryogenesis, regulation of Npm histone binding is critical for its function in storing and releasing maternal histones to establish and maintain the zygotic epigenome. Here, we demonstrate that Xenopus laevis Npm post-translational modifications (PTMs specific to the oocyte and egg promote either histone deposition or sequestration, respectively. Mass spectrometry and Npm phosphomimetic mutations used in chromatin assembly assays identified hyperphosphorylation on the N-terminal tail as a critical regulator for sequestration. C-terminal tail phosphorylation and PRMT5-catalyzed arginine methylation enhance nucleosome assembly by promoting histone interaction with the second acidic tract of Npm. Electron microscopy reconstructions of Npm and TTLL4 activity toward the C-terminal tail demonstrate that oocyte- and egg-specific PTMs cause Npm conformational changes. Our results reveal that PTMs regulate Npm chaperoning activity by modulating Npm conformation and Npm-histone interaction, leading to histone sequestration in the egg.

  7. Enhanced top-down characterization of histone post-translational modifications

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Zhixin; Tolić, Nikola; Zhao, Rui; Moore, Ronald J.; Hengel, Shawna M.; Robinson, Errol W.; Stenoien, David L.; Wu, Si; Smith, Richard D.; Paša-Tolić, Ljiljana

    2012-01-01

    Background: Multiple post-translational modifications (PTMs) on core histones often work synergistically to fine tune chromatin structure and functions, generating a “histone code” that can be interpreted by a variety of chromatin interacting proteins. Although previous bottom-up and middle-down proteomic approaches have been developed for limited characterization of PTMs on histone N-terminal tails, high-throughput methods for comprehensive identification of PTMs distributed along the entire primary amino acid sequence are yet to be implemented. Results: Here we report a novel online two-dimensional liquid chromatography - tandem mass spectrometry (2D LC–MS/MS) platform for high-throughput and sensitive characterization of histone PTMs at the intact protein level. The metal-free LC system with reverse phase separation followed by weak cation exchange – hydrophilic interaction chromatography (WCX-HILIC) and online Orbitrap Velos tandem mass spectrometry allowed for unambiguous identification of over 700 histone isoforms from a single 2D LC–MS/MS analysis of 7.5 µg of purified core histones. In comparison with previous offline top-down analysis of H4, this online study identified 100 additional isoforms from 100-fold less sample. This platform enabled comprehensive characterization of histone modifications, including those beyond tail regions, with dramatically improved throughput and sensitivity compared to more traditional platforms. Isoforms identified included those with combinatorial PTMs extending well beyond the N-terminal tail regions as well as a large number of phosphorylated isoforms.

  8. No need to be HAMLET or BAMLET to interact with histones: binding of monomeric alpha-lactalbumin to histones and basic poly-amino acids.

    Science.gov (United States)

    Permyakov, Serge E; Pershikova, Irina V; Khokhlova, Tatyana I; Uversky, Vladimir N; Permyakov, Eugene A

    2004-05-18

    The ability of a specific complex of human alpha-lactalbumin with oleic acid (HAMLET) to induce cell death with selectivity for tumor and undifferentiated cells was shown recently to be mediated by interaction of HAMLET with histone proteins irreversibly disrupting chromatin structure [Duringer, C., et al. (2003) J. Biol. Chem. 278, 42131-42135]. Here we show that monomeric alpha-lactalbumin (alpha-LA) in the absence of fatty acids is also able to bind efficiently to the primary target of HAMLET, histone HIII, regardless of Ca(2+) content. Thus, the modification of alpha-LA by oleic acid is not required for binding to histones. We suggest that interaction of negatively charged alpha-LA with the basic histone stabilizes apo-alpha-LA and destabilizes the Ca(2+)-bound protein due to compensation for excess negative charge of alpha-LA's Ca(2+)-binding loop by positively charged residues of the histone. Spectrofluorimetric curves of titration of alpha-LA by histone H3 were well approximated by a scheme of cooperative binding of four alpha-LA molecules per molecule of histone, with an equilibrium dissociation constant of 1.0 microM. Such a stoichiometry of binding implies that the binding process is not site-specific with respect to histone and likely is driven by just electrostatic interactions. Co-incubation of positively charged poly-amino acids (poly-Lys and poly-Arg) with alpha-LA resulted in effects which were similar to those caused by histone HIII, confirming the electrostatic nature of the alpha-LA-histone interaction. In all cases that were studied, the binding was accompanied by aggregation. The data indicate that alpha-lactalbumin can be used as a basis for the design of antitumor agents, acting through disorganization of chromatin structure due to interaction between alpha-LA and histone proteins.

  9. Molecular functions of the histone acetyltransferase chaperone complex Rtt109-Vps75

    Energy Technology Data Exchange (ETDEWEB)

    Berndsen, Christopher E; Tsubota, Toshiaki; Lindner, Scott E; Lee, Susan; Holton, James M; Kaufman, Paul D; Keck, James L; Denu, John M [UMASS, MED; (UCB); (UW-MED)

    2010-01-12

    Histone acetylation and nucleosome remodeling regulate DNA damage repair, replication and transcription. Rtt109, a recently discovered histone acetyltransferase (HAT) from Saccharomyces cerevisiae, functions with the histone chaperone Asf1 to acetylate lysine K56 on histone H3 (H3K56), a modification associated with newly synthesized histones. In vitro analysis of Rtt109 revealed that Vps75, a Nap1 family histone chaperone, could also stimulate Rtt109-dependent acetylation of H3K56. However, the molecular function of the Rtt109-Vps75 complex remains elusive. Here we have probed the molecular functions of Vps75 and the Rtt109-Vps75 complex through biochemical, structural and genetic means. We find that Vps75 stimulates the kcat of histone acetylation by {approx}100-fold relative to Rtt109 alone and enhances acetylation of K9 in the H3 histone tail. Consistent with the in vitro evidence, cells lacking Vps75 showed a substantial reduction (60%) in H3K9 acetylation during S phase. X-ray structural, biochemical and genetic analyses of Vps75 indicate a unique, structurally dynamic Nap1-like fold that suggests a potential mechanism of Vps75-dependent activation of Rtt109. Together, these data provide evidence for a multifunctional HAT-chaperone complex that acetylates histone H3 and deposits H3-H4 onto DNA, linking histone modification and nucleosome assembly.

  10. Histone profiles in cancer.

    Science.gov (United States)

    Riedel, Simone S; Neff, Tobias; Bernt, Kathrin M

    2015-10-01

    While DNA abnormalities have long been recognized as the cause of cancer, the contribution of chromatin is a relatively recent discovery. Excitement in the field of cancer epigenetics is driven by 3 key elements: 1. Chromatin may play an active and often critical role in controlling gene expression, DNA stability and cell identity. 2. Chromatin modifiers are frequent targets of DNA aberrations, in some cancers reaching near 100%. Particularly in cancers with low rates of DNA mutations, the key "driver" of malignancy is often a chromatin modifier. 3. Cancer-associated aberrant chromatin is amenable to pharmacologic modulation. This has sparked the rapidly expanding development of small molecules targeting chromatin modifiers or reader domains, several of which have shown promise in clinical trials. In parallel, technical advances have greatly enhanced our ability to perform comprehensive chromatin/histone profiling. Despite the discovery that distinct histone profiles are associated with prognostic subgroups, and in some instances may point towards an underlying aberration that can be targeted, histone profiling has not entered clinical diagnostics. Even eligibility for clinical trials targeting chromatin hinges on traditional histologic or DNA-based molecular criteria rather than chromatin profiles. This review will give an overview of the philosophical debate around the role of histones in controlling or modulating gene expression and discuss the most common techniques for histone profiling. In addition, we will provide prominent examples of aberrantly expressed or mutated chromatin modifiers that result in either globally or locally aberrant histone profiles, and that may be promising therapeutic targets. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Middle-down hybrid chromatography/tandem mass spectrometry workflow for characterization of combinatorial post-translational modifications in histones

    DEFF Research Database (Denmark)

    Sidoli, Simone; Schwämmle, Veit; Ruminowicz, Chrystian

    2014-01-01

    Scale software to extract, filter and analyze MS/MS data, including quantification of co-fragmenting isobaric polypeptide species. We characterized histone tails derived from murine embryonic stem cells (ESCs) knockout in Suppressor of Zeste (Suz12(-/-) ) and quantified 256 combinatorial histone marks...... combinatorial marks. We conclude that the inactivation of Suz12 is associated with changes in the abundance of not only H3K27 methylation but also multiple other PTMs in histone H3 tails. This article is protected by copyright. All rights reserved....

  12. Schistosoma mansoni histones: from transcription to chromatin regulation; an in silico analysis.

    Science.gov (United States)

    Anderson, Letícia; Pierce, Raymond J; Verjovski-Almeida, Sergio

    2012-06-01

    Schistosoma mansoni is a human endoparasite with a complex life cycle that also infects an invertebrate mollusk intermediate host and exhibits many diverse phenotypes. Its complexity is reflected in a large genome and different transcriptome profiles specific to each life cycle stage. Epigenetic regulation of gene expression such as the post-translational modification of histones has a significant impact on phenotypes, and this information storage function resides primarily at histone tails, which results in a varied histone code. Evidence of transcription of the different histone families at all life stages of the parasite was detected by a survey of transcriptome databases; manual curation of each gene prediction at the genome sequence level showed errors in the coding sequences of three of them. The biogenesis of histones is coupled to DNA replication, and a detailed in silico analysis of the specialized machinery of histone mRNA processing in the S. mansoni genome reveals that it is as conserved as in other eukaryotes, consisting in transcription factors and stem-loop binding proteins which recognize the stem loop structure at the histone mRNA 3'UTR. Histone modifying enzymes (HMEs) such as histone acetyltransferases, methyltransferases and deacetylases (HDACs) have been described in S. mansoni, and their potential as new therapeutic targets was evidenced with the apoptotic phenotype that resulted from HDAC inhibition. However, the overall regulation of transcription coupled with gene expression profiles correlated to histone modifications has not yet been characterized. Besides the interaction of HMEs with histones, many factors involved in cellular processes are known to bind to histones, and were identified here by an in silico analysis of the S. mansoni genome. Knowledge of the histone families opens up perspectives for further studies that will lead to a better identification of their post-translational modifications, their gene regulation and to the

  13. A role for CARM1-mediated histone H3 arginine methylation in protecting histone acetylation by releasing corepressors from chromatin.

    Directory of Open Access Journals (Sweden)

    Jing Wu

    Full Text Available Arginine methylation broadly occurs in histones and has been linked to transcriptional regulation, cell cycle regulation and DNA repair. While numerous proteins (histone code effectors that specifically recognize or read the methylated lysine residues in core histones have been identified, little is known for effectors specific for methylated arginines in histones. In this study, we attempted to identify effector(s recognizing asymmetrically methylated R17 and R26 in H3, which are catalyzed by CARM1/PRMT4, through an unbiased biochemical approach. Although we have yet to identify such effector using this approach, we find that these modifications function cooperatively with histone acetylation to inhibit the binding of the nucleosome remodeling and deacetylase complex (NuRD and TIF1 family corepressors to H3 tail in vitro. In support of this finding, we show that overexpression of CARM1 in 293 T cells leads to reduced association of NuRD with chromatin, whereas knockdown of CARM1 in HeLa cells leads to increased association of NuRD with chromatin and decreased level of histone acetylation. Furthermore, in the Carm1-/- MEF cells there is an increased association of NuRD and TIF1β with chromatin and a global decrease in histone acetylation. By chromatin immunoprecipitation assay, we show that overexpression of CARM1 results in reduced association of NuRD complex and TIF1β with an episomal reporter and that CARM1 is required in MEF cells for LPS-induced dissociation of NuRD from a NF-κb target gene. Taking together, our study provides evidence for a role of CARM1-mediated arginine methylation in regulation of histone acetylation and transcription: facilitating transcription by discharging corepressors from chromatin.

  14. Nucleosome assembly protein-1 is a linker histone chaperone in Xenopus eggs.

    Science.gov (United States)

    Shintomi, Keishi; Iwabuchi, Mari; Saeki, Hideaki; Ura, Kiyoe; Kishimoto, Takeo; Ohsumi, Keita

    2005-06-07

    In eukaryotic cells, genomic DNA is primarily packaged into nucleosomes through sequential ordered binding of the core and linker histone proteins. The acidic proteins termed histone chaperones are known to bind to core histones to neutralize their positive charges, thereby facilitating their proper deposition onto DNA to assemble the core of nucleosomes. For linker histones, however, little has been known about the regulatory mechanism for deposition of linker histones onto the linker DNA. Here we report that, in Xenopus eggs, the linker histone is associated with the Xenopus homologue of nucleosome assembly protein-1 (NAP-1), which is known to be a chaperone for the core histones H2A and H2B in Drosophila and mammalian cells [Ito, T., Bulger, M., Kobayashi, R. & Kadonaga, J. T. (1996) Mol. Cell Biol. 16, 3112-3124; Chang, L., Loranger, S. S., Mizzen, C., Ernst, S. G., Allis, C. D. & Annunziato, A. T. (1997) Biochemistry 36, 469-480]. We show that NAP-1 acts as the chaperone for the linker histone in both sperm chromatin remodeling into nucleosomes and linker histone binding to nucleosome core dimers. In the presence of NAP-1, the linker histone is properly deposited onto linker DNA at physiological ionic strength, without formation of nonspecific aggregates. These results strongly suggest that NAP-1 functions as a chaperone for the linker histone in Xenopus eggs.

  15. Rapid purification of recombinant histones.

    Directory of Open Access Journals (Sweden)

    Henrike Klinker

    Full Text Available The development of methods to assemble nucleosomes from recombinant histones decades ago has transformed chromatin research. Nevertheless, nucleosome reconstitution remains time consuming to this day, not least because the four individual histones must be purified first. Here, we present a streamlined purification protocol of recombinant histones from bacteria. We termed this method "rapid histone purification" (RHP as it circumvents isolation of inclusion bodies and thereby cuts out the most time-consuming step of traditional purification protocols. Instead of inclusion body isolation, whole cell extracts are prepared under strongly denaturing conditions that directly solubilize inclusion bodies. By ion exchange chromatography, the histones are purified from the extracts. The protocol has been successfully applied to all four canonical Drosophila and human histones. RHP histones and histones that were purified from isolated inclusion bodies had similar purities. The different purification strategies also did not impact the quality of octamers reconstituted from these histones. We expect that the RHP protocol can be readily applied to the purification of canonical histones from other species as well as the numerous histone variants.

  16. Biochemical Analysis of Histone Succinylation

    Directory of Open Access Journals (Sweden)

    Atsushi Yokoyama

    2017-01-01

    Full Text Available Posttranslational modification (PTM of proteins is used to regulate protein activity and stability. Histone PTMs are regarded as some of the most important, as they can directly regulate gene expression through chromatin reorganization. Recently, histone proteins were found to undergo succinylation, adding to other well-known PTMs such as acetylation, methylation, and phosphorylation. However, there is little information regarding the enzyme which catalyzes histone lysine succinylation. In fact, it is unclear whether this reaction is enzymatic. In this study, we tested histone succinylation activity in vitro using cell nuclear extracts of HepG2 cells. Although whole nuclear extracts did not show histone succinylation activity, we found that an SP 1.0 M KCl fraction of nuclear extracts indeed had such activity. These data offer the first direct evidence that histone succinylation is an enzymatic PTM as are other histone codes in the nucleus.

  17. Absolute quantification of histone PTM marks by MRM-based LC-MS/MS.

    Science.gov (United States)

    Gao, Jun; Liao, Rijing; Yu, Yanyan; Zhai, Huili; Wang, Yingqi; Sack, Ragna; Peters, Antoine H F M; Chen, Jiajia; Wu, Haiping; Huang, Zheng; Hu, Min; Qi, Wei; Lu, Chris; Atadja, Peter; Oyang, Counde; Li, En; Yi, Wei; Zhou, Shaolian

    2014-10-07

    The N-terminal tails of core histones harbor the sites of numerous post-translational modifications (PTMs) with important roles in the regulation of chromatin structure and function. Profiling histone PTM marks provides data that help understand the epigenetics events in cells and their connections with cancer and other diseases. Our previous study demonstrated that specific derivatization of histone peptides by NHS propionate significantly improved their chromatographic performance on reversed phase columns for LC/MS analysis. As a step forward, we recently developed a multiple reaction monitoring (MRM) based LC-MS/MS method to analyze 42 targeted histone peptides. By using stable isotopic labeled peptides as internal standards that are spiked into the reconstituted solutions, this method allows to measure absolute concentration of the tryptic peptides of H3 histone proteins extracted from cancer cell lines. The method was thoroughly validated for the accuracy and reproducibility through analyzing recombinant histone proteins and cellular samples. The linear dynamic range of the MRM assays was achieved in 3 orders of magnitude from 1 nM to 1 μM for all targeted peptides. Excellent intrabatch and interbatch reproducibility (<15% CV) was obtained. This method has been used to study translocated NSD2 (a histone lysine methyltransferase that catalyzes the histone lysine 36 methylation) function with its overexpression in KMS11 multiple myeloma cells. From the results we have successfully quantitated both individual and combinatorial histone marks in parental and NSD2 selective knockout KMS11 cells.

  18. The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis

    Science.gov (United States)

    Zou, Tie; Yao, Annie Y.; Cooper, Marcus P.; Boyartchuk, Victor; Wang, Yong-Xu

    2012-01-01

    Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes. PMID:22719268

  19. Evidence for the implication of the histone code in building the genome structure.

    Science.gov (United States)

    Prakash, Kirti; Fournier, David

    2017-11-20

    Histones are punctuated with small chemical modifications that alter their interaction with DNA. One attractive hypothesis stipulates that certain combinations of these histone modifications may function, alone or together, as a part of a predictive histone code to provide ground rules for chromatin folding. We consider four features that relate histone modifications to chromatin folding: charge neutralisation, molecular specificity, robustness and evolvability. Next, we present evidence for the association among different histone modifications at various levels of chromatin organisation and show how these relationships relate to function such as transcription, replication and cell division. Finally, we propose a model where the histone code can set critical checkpoints for chromatin to fold reversibly between different orders of the organisation in response to a biological stimulus. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Cis and trans internucleosomal interactions of H3 and H4 tails in tetranucleosomes.

    Science.gov (United States)

    Nurse, Nathan P; Yuan, Chongli

    2015-01-01

    Chromatin structure and the transcriptional state of a gene can be modulated by modifications made on H3 and H4 tails of histones. Elucidating the internucleosomal interactions of these tails is vital to understanding epigenetic regulation. Differentiation between cis (intra-nucleosomal) and trans (inter-nucleosomal) interactions is often difficult with conventional techniques since H3 and H4 tails are flexible. The distinction, however, is important because these interactions model short- and long-range chromatin interactions respectively and have different bearings in biological processes. Combining FCS and PCH analysis, we can decouple the contribution of histone tails to cis and trans effects. A Mg(2+) gradient was employed to facilitate compaction and oligomerization of tetranucleosomes with H3 and/or H4 tail truncations. H3 tails were found to play a multifunctional role and exhibit the ability to partake in both attractive cis and trans interactions simultaneously. H4 tails partake in attractive cis and repulsive trans interactions at low [Mg(2+)]. These interactions are diminished at higher [Mg(2+)]. Simultaneous H3 and H4 tail truncation inhibited array oligomerization but maintained local array compaction at relatively high [Mg(2+)]. The established experimental approach can be extended to study the detailed molecular interactions mediated by epigenetic modification of flexible histone tails. © 2014 Wiley Periodicals, Inc.

  1. Probing the acetylation code of histone H4.

    Science.gov (United States)

    Lang, Diana; Schümann, Michael; Gelato, Kathy; Fischle, Wolfgang; Schwarzer, Dirk; Krause, Eberhard

    2013-10-01

    Histone modifications play crucial roles in genome regulation with lysine acetylation being implicated in transcriptional control. Here we report a proteome-wide investigation of the acetylation-dependent protein-protein interactions of the N-terminal tail of histone H4. Quantitative peptide-based affinity MS experiments using the SILAC approach determined the interactomes of H4 tails monoacetylated at the four known acetylation sites K5, K8, K12, and K16, bis-acetylated at K5/K12, triple-acetylated at K8/12/16 and fully tetra-acetylated. A set of 29 proteins was found enriched on the fully acetylated H4 tail while specific binders of the mono and bis-acetylated tails were barely detectable. These observations are in good agreement with earlier reports indicating that the H4 acetylation state establishes its regulatory effects in a cumulative manner rather than via site-specific recruitment of regulatory proteins. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control

    NARCIS (Netherlands)

    Tessadori, Federico; Giltay, Jacques C; Hurst, Jane A; Massink, Maarten P; Duran, Karen; Vos, Harmjan R; van Es, Robert M; Scott, Richard H; van Gassen, Koen L I; Bakkers, Jeroen; van Haaften, Gijs

    2017-01-01

    Covalent modifications of histones have an established role as chromatin effectors, as they control processes such as DNA replication and transcription, and repair or regulate nucleosomal structure. Loss of modifications on histone N tails, whether due to mutations in genes belonging to

  3. Histone variant innovation in a rapidly evolving chordate lineage

    Directory of Open Access Journals (Sweden)

    Jansen Pascal WTC

    2011-07-01

    Full Text Available Abstract Background Histone variants alter the composition of nucleosomes and play crucial roles in transcription, chromosome segregation, DNA repair, and sperm compaction. Modification of metazoan histone variant lineages occurs on a background of genome architecture that shows global similarities from sponges to vertebrates, but the urochordate, Oikopleura dioica, a member of the sister group to vertebrates, exhibits profound modification of this ancestral architecture. Results We show that a histone complement of 47 gene loci encodes 31 histone variants, grouped in distinct sets of developmental expression profiles throughout the life cycle. A particularly diverse array of 15 male-specific histone variants was uncovered, including a testes-specific H4t, the first metazoan H4 sequence variant reported. Universal histone variants H3.3, CenH3, and H2A.Z are present but O. dioica lacks homologs of macroH2A and H2AX. The genome encodes many H2A and H2B variants and the repertoire of H2A.Z isoforms is expanded through alternative splicing, incrementally regulating the number of acetylatable lysine residues in the functionally important N-terminal "charge patch". Mass spectrometry identified 40 acetylation, methylation and ubiquitylation posttranslational modifications (PTMs and showed that hallmark PTMs of "active" and "repressive" chromatin were present in O. dioica. No obvious reduction in silent heterochromatic marks was observed despite high gene density in this extraordinarily compacted chordate genome. Conclusions These results show that histone gene complements and their organization differ considerably even over modest phylogenetic distances. Substantial innovation among all core and linker histone variants has evolved in concert with adaptation of specific life history traits in this rapidly evolving chordate lineage.

  4. Novel E3 ubiquitin ligases that regulate histone protein levels in the budding yeast Saccharomyces cerevisiae.

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    Rakesh Kumar Singh

    Full Text Available Core histone proteins are essential for packaging the genomic DNA into chromatin in all eukaryotes. Since multiple genes encode these histone proteins, there is potential for generating more histones than what is required for chromatin assembly. The positively charged histones have a very high affinity for negatively charged molecules such as DNA, and any excess of histone proteins results in deleterious effects on genomic stability and cell viability. Hence, histone levels are known to be tightly regulated via transcriptional, posttranscriptional and posttranslational mechanisms. We have previously elucidated the posttranslational regulation of histone protein levels by the ubiquitin-proteasome pathway involving the E2 ubiquitin conjugating enzymes Ubc4/5 and the HECT (Homologous to E6-AP C-Terminus domain containing E3 ligase Tom1 in the budding yeast. Here we report the identification of four additional E3 ligases containing the RING (Really Interesting New Gene finger domains that are involved in the ubiquitylation and subsequent degradation of excess histones in yeast. These E3 ligases are Pep5, Snt2 as well as two previously uncharacterized Open Reading Frames (ORFs YKR017C and YDR266C that we have named Hel1 and Hel2 (for Histone E3 Ligases respectively. Mutants lacking these E3 ligases are sensitive to histone overexpression as they fail to degrade excess histones and accumulate high levels of endogenous histones on histone chaperones. Co-immunoprecipitation assays showed that these E3 ligases interact with the major E2 enzyme Ubc4 that is involved in the degradation related ubiquitylation of histones. Using mutagenesis we further demonstrate that the RING domains of Hel1, Hel2 and Snt2 are required for histone regulation. Lastly, mutants corresponding to Hel1, Hel2 and Pep5 are sensitive to replication inhibitors. Overall, our results highlight the importance of posttranslational histone regulatory mechanisms that employ multiple E3

  5. Novel insights into the plant histone code: lessons from ORC1.

    Science.gov (United States)

    Sanchez, María de la Paz; Gutierrez, Crisanto

    2009-05-16

    Gene expression control depends on the combinatorial presence of various posttranslational modifications of the N-terminal tail of histones, among which acetylation and methylation of lysine residues are the most conspicuous. Effector proteins have been identified that recognize specific histone modifications and transduce the information of the histone code into different degrees of chromatin compaction in either facultative or constitutive heterochromatin. In addition, they also impinge on transcriptional control, either activation or repression, of euchromatic genes. However, a large variety of effector proteins lead to different gene expression readouts. This is complicated by accumulating evidence showing that the consequences of various histone modifications differ among animals and plants. Given the conservation of histone marks, and histone modification enzymes, this has evolutionary implications as to how they are interpreted differently in different organisms. One example that illustrates such diversity of the histone code is the large subunit of the origin recognition complex, ORC1. In plants, but not in yeast and animal cells, ORC1 functions as a transcriptional activator of a subset of target genes and is a plant homeodomain (PHD)-containing protein that binds to histone H3K4me3 residues.

  6. Histone methyltransferases in cancer

    DEFF Research Database (Denmark)

    Albert, Mareike; Helin, Kristian

    2009-01-01

    Cancer is perceived as a heterogeneous group of diseases that is characterized by aberrant patterns of gene expression. In the last decade, an increasing amount of data has pointed to a key role for epigenetic alterations in human cancer. In this review, we focus on a subclass of epigenetic...... regulators, namely histone methyltransferases (HMTs). Several HMTs have been linked to different types of cancer; however, in most cases we only have limited knowledge regarding the molecular mechanisms by which the HMTs contribute to disease development. We summarize the current knowledge regarding some...

  7. Histone deacetylases and atherosclerosis.

    Science.gov (United States)

    Zheng, Xia-xia; Zhou, Tian; Wang, Xin-An; Tong, Xiao-hong; Ding, Jia-wang

    2015-06-01

    Atherosclerosis is the most common pathological process that leads to cardiovascular diseases, a disease of large- and medium-sized arteries that is characterized by a formation of atherosclerotic plaques consisting of necrotic cores, calcified regions, accumulated modified lipids, smooth muscle cells (SMCs), endothelial cells, leukocytes, and foam cells. Recently, the question about how to suppress the occurrence of atherosclerosis and alleviate the progress of cardiovascular disease becomes the hot topic. Accumulating evidence suggests that histone deacetylases(HDACs) play crucial roles in arteriosclerosis. This review summarizes the effect of HDACs and HDAC inhibitors(HDACi) on the progress of atherosclerosis. Copyright © 2015. Published by Elsevier Ireland Ltd.

  8. Investigation Of A Transient Energetic Charge Exchange Fux Enhancement ('spike-on-tail') Observed In Neutral-beam-heated H-mode Discharges In The National Spherical Torus Experiment

    Energy Technology Data Exchange (ETDEWEB)

    Medley et al, S S

    2011-08-04

    In the National Spherical Torus Experiment (NSTX), a large increase in the charge exchange neutral flux localized at the Neutral Beam (NB) injection full energy is measured by the E||B (superimposed parallel electric and magnetic fields) Neutral Particle Analyzer (NPA). Termed the High-Energy Feature (HEF), it appears on the NB-injected energetic ion spectrum only in discharges where tearing or kink-type modes (f < 50 kHz) are absent, Toroidal Alfvén Eigenmode (TAE) activity (f ~ 50 - 150 kHz) is weak and Global Alfvén Eigenmode (GAE) activity (f ~ 400 – 1000 kHz) is robust. Compressional Alfvén eigenmode (CAE) activity (f > 1000 kHz) is usually sporadic or absent during the HEF event. The HEF exhibits growth times of Δt ~ 20 - 80 ms, durations of ~ 100 – 600 ms and peak-to-base flux ratios up to H = Fmax /Fmin ~ 10. In infrequent cases, a slowing down distribution below the HEF energy can develop that continues to evolve over periods > 100 ms, a time scale long compared with the typical fast ion equilibration times. HEFs are Transient energetic charge exchange flux enhancement ('spike-on-tail') 2 observed only in H-mode (not L-mode) discharges with injected power Pb ≥ 4 MW and in the pitch range χ = vll /v ~ 0.7 – 0.9; i.e. only for passing particles. Increases of ~ 10 - 30 % in the measured neutron yield and total stored energy that are observed to coincide with the feature appear to be driven by concomitant broadening of measured Te(r), Ti(r) and ne(r) profiles and not the HEF itself. While the HEF has minimal impact on plasma performance, it nevertheless poses a challenging wave-particle interaction phenomenon to understand. Candidate mechanisms for HEF formation are developed based on quasilinear theory of wave-particle interaction. The only mechanism found to lead to the large NPA flux ratios, H = Fmax /Fmin , observed in NSTX is the quasilinear evolution of the energetic ion distribution, Fb(E,χ,r), in phase space and the concomitant

  9. Antibody-free reading of the histone code using a simple chemical sensor array.

    Science.gov (United States)

    Minaker, Samuel A; Daze, Kevin D; Ma, Manuel C F; Hof, Fraser

    2012-07-18

    The histone code refers to the complex network of histone post-translational modifications that control gene expression and are of high interest as drivers of a large number of human diseases. We report here on a mix-and-match toolkit of readily available dyes and calixarene host molecules that can be combined to form dye-displacement sensors that respond to a wide variety of cationic peptides. Using the data from only two or three such simple supramolecular sensors as a chemical sensor array produces fingerprints of data that discriminate robustly among many kinds of histone code elements. "Reads" that are accomplished include the discrimination of unmethylated, mono-, di-, and trimethylated lysines on a single histone tail sequence, identification of different modifications and combinations of modifications on a single histone tail sequence, identification of a single modification type in several different sequence contexts, and identification of isomeric dimethylarginine modifications. Reads that are sometimes troublesome for antibodies are achieved. We also report on the ability of the sensor array to report simultaneously on the concentrations and identities of histone modifications. This sensor array discriminates between post-translationally modified analytes without being limited to partners that contain a single, programmed binding interaction.

  10. Structural insight into histone recognition by the ING PHD fingers.

    Science.gov (United States)

    Champagne, Karen S; Kutateladze, Tatiana G

    2009-05-01

    The Inhibitor of Growth (ING) tumor suppressors are implicated in oncogenesis, control of DNA damage repair, cellular senescence and apoptosis. All members of the ING family contain unique amino-terminal regions and a carboxy-terminal plant homeodomain (PHD) finger. While the amino-terminal domains associate with a number of protein effectors including distinct components of histone deacetylase (HDAC) and histone acetyltransferase (HAT) complexes, the PHD finger binds strongly and specifically to histone H3 trimethylated at lysine 4 (H3K4me3). In this review we describe the molecular mechanism of H3K4me3 recognition by the ING1-5 PHD fingers, analyze the determinants of the histone specificity and compare the biological activities and structures within subsets of PHD fingers. The atomic-resolution structures of the ING PHD fingers in complex with a H3K4me3 peptide reveal that the histone tail is bound in a large and deep binding site encompassing nearly one-third of the protein surface. An extensive network of intermolecular hydrogen bonds, hydrophobic and cation-pi contacts, and complementary surface interactions coordinate the first six residues of the H3K4me3 peptide. The trimethylated Lys4 occupies an elongated groove, formed by the highly conserved aromatic and hydrophobic residues of the PHD finger, whereas the adjacent groove accommodates Arg2. The two grooves are connected by a narrow channel, the small size of which defines the PHD finger's specificity, excluding interactions with other modified histone peptides. Binding of the ING PHD fingers to H3K4me3 plays a critical role in regulating chromatin acetylation. The ING proteins function as tethering molecules that physically link the HDAC and HAT enzymatic complexes to chromatin. In this review we also highlight progress recently made in understanding the molecular basis underlying biological and tumorigenic activities of the ING tumor suppressors.

  11. Identification and Characterization of Histone Deacetylases in Tomato (Solanum lycopersicum

    Directory of Open Access Journals (Sweden)

    Linmao eZhao

    2015-01-01

    Full Text Available Histone acetylation and deacetylation at the N-terminus of histone tails play crucial roles in the regulation of eukaryotic gene activity. Histone acetylation and deacetylation are catalyzed by histone acetyltransferases and histone deacetylases (HDACs, respectively. A growing number of studies have demonstrated the importance of histone deacetylation/acetylation on genome stability, transcriptional regulation, development and response to stress in Arabidopsis. However, the biological functions of HDACs in tomato have not been investigated previously. Fifteen HDACs identified from tomato (Solanum Lycopersicum can be grouped into RPD3/HDA1, SIR2 and HD2 families based on phylogenetic analysis. Meanwhile, ten members of the RPD3/HDA1 family can be further subdivided into four groups, namely Class I, Class II, Class III and Class IV. High similarities of protein sequences and conserved domains were identified among SlHDACs and their homologs in Arabidopsis. Most SlHDACs were expressed in all tissues examined with different transcript abundance. Transient expression in Arabidopsis protoplasts showed that SlHDA8, SlHDA1, SlHDA5, SlSRT1 and members of the HD2 family were localized to the nucleus, whereas SlHDA3 and SlHDA4 were localized in both the cytoplasm and nucleus. The difference in the expression patterns and subcellular localization of SlHDACs suggest that they may play distinct functions in tomato. Furthermore, we found that three members of the RPD3/HDA1 family, SlHDA1, SIHDA3 and SlHDA4, interacted with TAG1 (TOMATO AGAMOUS1 and TM29 (TOMATO MADS BOX29, two MADS-box proteins associated with tomato reproductive development,indicating that these HDACs may be involved in gene regulation in reproductive development.

  12. Tailings treatment and nano-particles

    Energy Technology Data Exchange (ETDEWEB)

    McEachern, P.; Burkus, Z.; Yu, T.; Ulrich, A.; Zhu, D. [Alberta Environment, Edmonton, AB (Canada)

    2009-07-01

    Oil sands fluid tailings are heterodispersed colloidal and suspended particles comprised of hydrophilic clays, metal oxides, organic acids, and hydration shells that create weak gels. Approximately 3 per cent of the total tailings stream are particles less than 0.2 {mu}m. Smaller fines are mobile with a high charge, and have a reactive surface that attracts organics and heavy metals. The fines also stick to bitumen and inhibit recovery. The particles in clays in tailings are typically less than 2 {mu}m. The multivalent ion increase the tendency for gelling. Treatment processes for fluid fine tailings include flocculation, chemical oxidation, and biological fermentation oxidation processes. Large polyacrylamides are used to capture fines in cross-bridged structures, while inorganic gels are used to hold water. Exopolysaccharides are used in mature fine tailings remediation processes. Other nanotechnology processes for tailings include photo-catalyzed oxidation, ozone pre-treatment; and zero valent ion treatments. Biotreatment researchers are now exploring the use of engineered microbially-mediated wastewater treatment technologies to accelerate oil sands tailings consolidation. Organic coagulants are also being considered as a means of consolidating tailings. It was concluded that various engineering reactors are now being investigated in order to accelerate microbial transformations. tabs., figs.

  13. Histone-modifying enzymes, histone modifications and histone chaperones in nucleosome assembly: Lessons learned from Rtt109 histone acetyltransferases

    Science.gov (United States)

    Dahlin, Jayme L; Chen, Xiaoyue; Walters, Michael A.; Zhang, Zhiguo

    2015-01-01

    During DNA replication, nucleosomes ahead of replication forks are disassembled to accommodate replication machinery. Following DNA replication, nucleosomes are then reassembled onto replicated DNA using both parental and newly synthesized histones. This process, termed DNA replication-coupled nucleosome assembly (RCNA), is critical for maintaining genome integrity and for the propagation of epigenetic information, dysfunctions of which have been implicated in cancers and aging. In recent years, it has been shown that RCNA is carefully orchestrated by a series of histone modifications, histone chaperones and histone-modifying enzymes. Interestingly, many features of RCNA are also found in processes involving DNA replication-independent nucleosome assembly like histone exchange and gene transcription. In yeast, histone H3 lysine K56 acetylation (H3K56ac) is found in newly synthesized histone H3 and is critical for proper nucleosome assembly and for maintaining genomic stability. The histone acetyltransferase (HAT) regulator of Ty1 transposition 109 (Rtt109) is the sole enzyme responsible for H3K56ac in yeast. Much research has centered on this particular histone modification and histone-modifying enzyme. This Critical Review summarizes much of our current understanding of nucleosome assembly and highlights many important insights learned from studying Rtt109 HATs in fungi. We highlight some seminal features in nucleosome assembly conserved in mammalian systems and describe some of the lingering questions in the field. Further studying fungal and mammalian chromatin assembly may have important public health implications, including deeper understandings of human cancers and aging as well as the pursuit of novel anti-fungal therapies. PMID:25365782

  14. A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Chun-Min; Wang, Jiyong; Xu, Ke; Chen, Huijie; Yue, Jia-Xing; Andrews, Stuart; Moresco, James J.; Yates, John R.; Nagy, Peter L.; Tong, Liang; Jia, Songtao

    2016-09-20

    Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.

  15. The chromatin regulatory code: Beyond a histone code

    Science.gov (United States)

    Lesne, A.

    2006-03-01

    In this commentary on the contribution by Arndt Benecke in this issue, I discuss why the notion of “chromatin code” introduced and elaborated in this paper is to be preferred to that of “histone code”. Speaking of a code as regards nucleosome conformation and histone tail post-translational modifications only makes sense within the chromatin fiber, where their physico-chemical features can be translated into regulatory programs at the genome level, by means of a complex, multi-level interplay with the fiber architecture and dynamics settled in the course of Evolution. In particular, this chromatin code presumably exploits allosteric transitions of the chromatin fiber. The chromatin structure dependence of its translation suggests two alternative modes of transcription initiation regulation, also proposed in the paper by A. Benecke in this issue for interpreting strikingly bimodal micro-array data.

  16. Heavy tails of OLS

    DEFF Research Database (Denmark)

    Mikosch, Thomas Valentin; de Vries, Casper

    2013-01-01

    Suppose the tails of the noise distribution in a regression exhibit power law behavior. Then the distribution of the OLS regression estimator inherits this tail behavior. This is relevant for regressions involving financial data. We derive explicit finite sample expressions for the tail...

  17. TRIM24 Links a Non-canonical Histone Signature to Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    W Tsai; Z Wang; T Yiu; K Akdemir; W Xia; S Winter; C Tsai; X Shi; D Schwarzer; et al.

    2011-12-31

    Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.

  18. Chromatin replication and histone dynamics

    DEFF Research Database (Denmark)

    Alabert, Constance; Jasencakova, Zuzana; Groth, Anja

    2017-01-01

    organization into chromatin. We reveal how specialized replication-coupled mechanisms rapidly assemble newly synthesized DNA into nucleosomes, while the complete restoration of chromatin organization including histone marks is a continuous process taking place throughout the cell cycle. Because failure...

  19. Histone chaperone networks shaping chromatin function

    DEFF Research Database (Denmark)

    Hammond, Colin; Strømme, Caroline Bianchi; Huang, Hongda

    2017-01-01

    The association of histones with specific chaperone complexes is important for their folding, oligomerization, post-translational modification, nuclear import, stability, assembly and genomic localization. In this way, the chaperoning of soluble histones is a key determinant of histone availabili...... chaperone network and via co-chaperone complexes to match histone supply with demand, thereby promoting proper nucleosome assembly and maintaining epigenetic information by recycling modified histones evicted from chromatin....

  20. Systems Level Analysis of Histone H3 Post-translational Modifications (PTMs) Reveals Features of PTM Crosstalk in Chromatin Regulation*

    Science.gov (United States)

    Schwämmle, Veit; Sidoli, Simone; Ruminowicz, Chrystian; Wu, Xudong; Lee, Chung-Fan; Helin, Kristian; Jensen, Ole N.

    2016-01-01

    Histones are abundant chromatin constituents carrying numerous post-translational modifications (PTMs). Such PTMs mediate a variety of biological functions, including recruitment of enzymatic readers, writers and erasers that modulate DNA replication, transcription and repair. Individual histone molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse embryonic stem cells (mESCs) knocked out in components of the Polycomb Repressive Complex 2 (PRC2, Suz12−/−), PRC1 (Ring1A/B−/−) and (Dnmt1/3a/3b−/−) we performed comprehensive PTM analysis of histone H3 tails (50 aa) by utilizing quantitative middle-down proteome analysis by tandem mass spectrometry. We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37me. Integration of the H3 data with RNAseq data by coabundance clustering analysis of histone PTMs and histone modifying enzymes revealed correlations between PTM and enzyme levels. We conclude that middle-down proteomics is a powerful tool to determine conserved or dynamic interdependencies between histone marks, which paves the way for detailed investigations of the histone code. Histone H3 PTM data is publicly available in the CrossTalkDB repository at http

  1. Systems Level Analysis of Histone H3 Post-translational Modifications (PTMs) Reveals Features of PTM Crosstalk in Chromatin Regulation.

    Science.gov (United States)

    Schwämmle, Veit; Sidoli, Simone; Ruminowicz, Chrystian; Wu, Xudong; Lee, Chung-Fan; Helin, Kristian; Jensen, Ole N

    2016-08-01

    Histones are abundant chromatin constituents carrying numerous post-translational modifications (PTMs). Such PTMs mediate a variety of biological functions, including recruitment of enzymatic readers, writers and erasers that modulate DNA replication, transcription and repair. Individual histone molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse embryonic stem cells (mESCs) knocked out in components of the Polycomb Repressive Complex 2 (PRC2, Suz12(-/-)), PRC1 (Ring1A/B(-/-)) and (Dnmt1/3a/3b(-/-)) we performed comprehensive PTM analysis of histone H3 tails (50 aa) by utilizing quantitative middle-down proteome analysis by tandem mass spectrometry. We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37me. Integration of the H3 data with RNAseq data by coabundance clustering analysis of histone PTMs and histone modifying enzymes revealed correlations between PTM and enzyme levels. We conclude that middle-down proteomics is a powerful tool to determine conserved or dynamic interdependencies between histone marks, which paves the way for detailed investigations of the histone code. Histone H3 PTM data is publicly available in the CrossTalkDB repository at http

  2. Epigenetic histone code and autoimmunity.

    Science.gov (United States)

    Dieker, Jürgen; Muller, Sylviane

    2010-08-01

    The multiple inter-dependent post-translational modifications of histones represent fine regulators of chromatin dynamics. These covalent modifications, including phosphorylation, acetylation, ubiquitination, deimination, and methylation, affect therefore the numerous processes involving chromatin, such as replication, repair, transcription, genome stability, and cell death. Specific enzymes introducing modified residues in histones are precisely regulated, and a single amino acid residue can be subjected to a single or several, independent modifications. Disruption of histone post-translational modifications perturbs the pattern of gene expression, which may result in disease manifestations. It has become evident in recent years that apoptosis-modified histones exert a central role in the induction of autoimmunity, for example in systemic lupus erythematosus and rheumatoid arthritis. Certain histone post-translational modifications are linked to cell death (apoptotic and non-apoptotic cell death) and might be involved in lupus in the activation of normally tolerant lymphocyte subpopulations. In this review, we discuss how these modifications can affect the antigenicity and immunogenicity of histones with potential consequences in the pathogenesis of autoimmune diseases.

  3. Structure and Histone Binding Properties of the Vps75-Rtt109 Chaperone-Lysine Acetyltransferase Complex

    Energy Technology Data Exchange (ETDEWEB)

    Su, Dan; Hu, Qi; Zhou, Hui; Thompson, James R.; Xu, Rui-Ming; Zhang, Zhiguo; Mer, Georges (Mayo); (Chinese Aca. Sci.)

    2011-11-02

    The histone chaperone Vps75 presents the remarkable property of stimulating the Rtt109-dependent acetylation of several histone H3 lysine residues within (H3-H4){sub 2} tetramers. To investigate this activation mechanism, we determined x-ray structures of full-length Vps75 in complex with full-length Rtt109 in two crystal forms. Both structures show similar asymmetric assemblies of a Vps75 dimer bound to an Rtt109 monomer. In the Vps75-Rtt109 complexes, the catalytic site of Rtt109 is confined to an enclosed space that can accommodate the N-terminal tail of histone H3 in (H3-H4){sub 2}. Investigation of Vps75-Rtt109-(H3-H4)2 and Vps75-(H3-H4)2 complexes by NMR spectroscopy-probed hydrogen/deuterium exchange suggests that Vps75 guides histone H3 in the catalytic enclosure. These findings clarify the basis for the enhanced acetylation of histone H3 tail residues by Vps75-Rtt109.

  4. Electrodynamics of Radiating Charges

    Directory of Open Access Journals (Sweden)

    Øyvind Grøn

    2012-01-01

    Full Text Available The theory of electrodynamics of radiating charges is reviewed with special emphasis on the role of the Schott energy for the conservation of energy for a charge and its electromagnetic field. It is made clear that the existence of radiation from a charge is not invariant against a transformation between two reference frames that has an accelerated motion relative to each other. The questions whether the existence of radiation from a uniformly accelerated charge with vanishing radiation reaction force is in conflict with the principle of equivalence and whether a freely falling charge radiates are reviewed. It is shown that the resolution of an electromagnetic “perpetuum mobile paradox” associated with a charge moving geodetically along a circular path in the Schwarzschild spacetime requires the so-called tail terms in the equation of motion of a charged particle.

  5. Cracking the enigmatic linker histone code.

    Science.gov (United States)

    Godde, James S; Ura, Kiyoe

    2008-03-01

    Recently, the existence of a 'histone code' has been proposed to explain the link between the covalent chemical modification of histone proteins and the epigenetic regulation of gene activity. Although the role of the four 'core' histones has been extensively studied, little is known about the involvement of the linker histone, histone H1 and its variants, in this code. For many years, few sites of chemical modification had been mapped in linker histones, but this has changed recently with the use of functional proteomic techniques, principally mass spectrometry, to characterize these modifications. The functionality of many of these sites, however, remains to be determined.

  6. Immunostaining analysis of tissue cultured cells and tissue sections using phospho-Histone H3 (Serine 10) antibody.

    Science.gov (United States)

    Padmanabhan, Jaya

    2015-01-01

    Post-translational modifications of histones play an important role in regulation of gene expression through condensation and decondensation of chromatin structure. These modifications include acetylation, methylation, phosphorylation and ubiquitination. Phosphorylation on histones is associated with cellular responses such as DNA damage, transcription, chromatin compaction and mitosis or meiosis. One of the most extensively studied modifications of histones is the Serine 10 phosphorylation on histone H3 N-terminal tail. This specific phosphorylation on Histone H3 has been associated with condensation and transcriptional inactivation of mitotic chromosomes, but recent studies have suggested a role for this specific phosphorylation in chromatin relaxation and activation of transcription in interphase cells. Co-immunostaining analysis of cells using antibodies specific to serine 10P-Histone H3 together with those to cell cycle specific markers will allow us to determine the nature of phosphorylation in a cell cycle-specific manner. In a complex system, such as tissue specimens, analysis using P-Histone H3 and a cell type specific antibody will allow identification of specific cells that are affected by this histone modification. This is of particular interest in the field of cancer biology or neurobiology where identification or quantification of the transcriptionally active or mitotic cells will enable one to evaluate the progression of the disease development. The protocol described here provides details on how co-immunostaining and analysis can be performed in tissue cultured cells or tissue sections.

  7. Histone Lysine Methylation and Neurodevelopmental Disorders

    Directory of Open Access Journals (Sweden)

    Jeong-Hoon Kim

    2017-06-01

    Full Text Available Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases.

  8. Histone variants: emerging players in cancer biology

    Science.gov (United States)

    Vardabasso, Chiara; Hasson, Dan; Ratnakumar, Kajan; Chung, Chi-Yeh; Duarte, Luis F.

    2014-01-01

    Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology. PMID:23652611

  9. The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

    NARCIS (Netherlands)

    van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G J; Ourailidou, Maria Eleni; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J; Dekker, Frank J

    2016-01-01

    Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as

  10. H4 Tails Potentially Produce the Diversity in the Orientation of Two Nucleosomes.

    Science.gov (United States)

    Ishida, Hisashi; Kono, Hidetoshi

    2017-09-05

    Histone tails play an important role in internucleosomal interaction and chromatin compaction. To understand how the H4 tails are involved in the internucleosomal interaction, an adaptively biased molecular dynamics simulation of 63 models of two stacked nucleosomes, each with the H4 tails in different locations, was carried out. This simulation generated a variety of orientations of the separated nucleosomes depending on the formation of the H4 tail bridge between the H4 tails and the DNA of the neighboring nucleosomes. For the models that showed distinctive orientations of the two nucleosomes, the free energies of the separation of the nucleosomes were further investigated using umbrella sampling simulations. The attractive force between the nucleosomes was estimated from the free energies; the force when two H4 tail bridges formed varied from 36 to 63 pN, depending on the formation of the H4 tail-bridge and the interfacial interaction, whereas the force reduced to 15-18 pN after either one of the H4 tail bridges had broken, regardless of the conformation of the H4 tail. Additional simulations of the nucleosomes show that when the H4 tail was truncated, the force between the nucleosomes became repulsive (from-3 to -7 pN). We concluded that the H4 tails potentially produce the diversity in the orientation of the two nucleosomes, which would contribute to the polymorphism of the chromatin structure. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  11. Intracellular delivery of acetyl-histone peptides inhibits native bromodomain-chromatin interactions and impairs mitotic progression

    Science.gov (United States)

    Nishiyama, Akira; Mochizuki, Kazuki; Mueller, Florian; Karpova, Tatiana; McNally, James G.; Ozato, Keiko

    2008-01-01

    Bromodomains present in Brd4 and other chromatin proteins interact with acetylated histones to regulate transcription and cell growth. To study Brd4-chromatin interactions in vivo, histone H4 tail peptides were fused to a synthetic protein transduction domain (PTD) derived from the human immunodeficiency virus Tat and delivered into cultured cells. Acetyl-H4 peptides, but not unacetylated H4 peptides inhibited real time Brd4-chromatin interactions in living cells as assessed by fluorescence recovery after photobleaching assays. The acetyl-H4 peptides also inhibited an interaction of Brd4 with chromosomes during mitosis and reduced cell growth potential. Together, PTD-based delivery of histone tail peptides offers a novel means to study the mechanism and biological significance of bromodomain-chromatin interactions in vivo. PMID:18396160

  12. Genome-wide integration on transcription factors, histone acetylation and gene expression reveals genes co-regulated by histone modification patterns.

    Directory of Open Access Journals (Sweden)

    Yayoi Natsume-Kitatani

    Full Text Available N-terminal tails of H2A, H2B, H3 and H4 histone families are subjected to posttranslational modifications that take part in transcriptional regulation mechanisms, such as transcription factor binding and gene expression. Regulation mechanisms under control of histone modification are important but remain largely unclear, despite of emerging datasets for comprehensive analysis of histone modification. In this paper, we focus on what we call genetic harmonious units (GHUs, which are co-occurring patterns among transcription factor binding, gene expression and histone modification. We present the first genome-wide approach that captures GHUs by combining ChIP-chip with microarray datasets from Saccharomyces cerevisiae. Our approach employs noise-robust soft clustering to select patterns which share the same preferences in transcription factor-binding, histone modification and gene expression, which are all currently implied to be closely correlated. The detected patterns are a well-studied acetylation of lysine 16 of H4 in glucose depletion as well as co-acetylation of five lysine residues of H3 with H4 Lys12 and H2A Lys7 responsible for ribosome biogenesis. Furthermore, our method further suggested the recognition of acetylated H4 Lys16 being crucial to histone acetyltransferase ESA1, whose essential role is still under controversy, from a microarray dataset on ESA1 and its bypass suppressor mutants. These results demonstrate that our approach allows us to provide clearer principles behind gene regulation mechanisms under histone modifications and detect GHUs further by applying to other microarray and ChIP-chip datasets. The source code of our method, which was implemented in MATLAB (http://www.mathworks.com/, is available from the supporting page for this paper: http://www.bic.kyoto-u.ac.jp/pathway/natsume/hm_detector.htm.

  13. Diversity and Divergence of Dinoflagellate Histone Proteins.

    Science.gov (United States)

    Marinov, Georgi K; Lynch, Michael

    2015-12-08

    Histone proteins and the nucleosomal organization of chromatin are near-universal eukaroytic features, with the exception of dinoflagellates. Previous studies have suggested that histones do not play a major role in the packaging of dinoflagellate genomes, although several genomic and transcriptomic surveys have detected a full set of core histone genes. Here, transcriptomic and genomic sequence data from multiple dinoflagellate lineages are analyzed, and the diversity of histone proteins and their variants characterized, with particular focus on their potential post-translational modifications and the conservation of the histone code. In addition, the set of putative epigenetic mark readers and writers, chromatin remodelers and histone chaperones are examined. Dinoflagellates clearly express the most derived set of histones among all autonomous eukaryote nuclei, consistent with a combination of relaxation of sequence constraints imposed by the histone code and the presence of numerous specialized histone variants. The histone code itself appears to have diverged significantly in some of its components, yet others are conserved, implying conservation of the associated biochemical processes. Specifically, and with major implications for the function of histones in dinoflagellates, the results presented here strongly suggest that transcription through nucleosomal arrays happens in dinoflagellates. Finally, the plausible roles of histones in dinoflagellate nuclei are discussed. Copyright © 2016 Marinov and Lynch.

  14. Diversity and Divergence of Dinoflagellate Histone Proteins

    Directory of Open Access Journals (Sweden)

    Georgi K. Marinov

    2016-02-01

    Full Text Available Histone proteins and the nucleosomal organization of chromatin are near-universal eukaroytic features, with the exception of dinoflagellates. Previous studies have suggested that histones do not play a major role in the packaging of dinoflagellate genomes, although several genomic and transcriptomic surveys have detected a full set of core histone genes. Here, transcriptomic and genomic sequence data from multiple dinoflagellate lineages are analyzed, and the diversity of histone proteins and their variants characterized, with particular focus on their potential post-translational modifications and the conservation of the histone code. In addition, the set of putative epigenetic mark readers and writers, chromatin remodelers and histone chaperones are examined. Dinoflagellates clearly express the most derived set of histones among all autonomous eukaryote nuclei, consistent with a combination of relaxation of sequence constraints imposed by the histone code and the presence of numerous specialized histone variants. The histone code itself appears to have diverged significantly in some of its components, yet others are conserved, implying conservation of the associated biochemical processes. Specifically, and with major implications for the function of histones in dinoflagellates, the results presented here strongly suggest that transcription through nucleosomal arrays happens in dinoflagellates. Finally, the plausible roles of histones in dinoflagellate nuclei are discussed.

  15. Dynamic and distinct histone modifications modulate the expression of key adipogenesis regulatory genes.

    Science.gov (United States)

    Zhang, Qiongyi; Ramlee, Muhammad Khairul; Brunmeir, Reinhard; Villanueva, Claudio J; Halperin, Daniel; Xu, Feng

    2012-12-01

    Histone modifications and their modifying enzymes are fundamentally involved in the epigenetic regulation of adipogenesis. This study aimed to define the roles of various histone modifications and their "division of labor" in fat cell differentiation. To achieve these goals, we examined the distribution patterns of eight core histone modifications at five key adipogenic regulatory genes, Pref-1, C/EBPβ, C/EBPα, PPARγ2 and aP2, during the adipogenesis of C3H 10T1/2 mouse mesenchymal stem cells (MSCs) and 3T3-L1 preadipocytes. We found that the examined histone modifications are globally stable throughout adipogenesis but show distinct and highly dynamic distribution patterns at specific genes. For example, the Pref-1 gene has lower levels of active chromatin markers and significantly higher H3 K27 tri-methylation in MSCs compared with committed preadipocytes; the C/EBPβ gene is enriched in active chromatin markers at its 3'-UTR; the C/EBPα gene is predominantly marked by H3 K27 tri-methylation in adipogenic precursor cells, and this repressive marker decreases dramatically upon induction; the PPARγ2 and aP2 genes show increased histone acetylation on both H3 and H4 tails during adipogenesis. Further functional studies revealed that the decreased level of H3 K27 tri-methylation leads to de-repression of Pref-1 gene, while the increased level of histone acetylation activates the transcription of PPARγ2 and aP2 genes. Moreover, the active histone modification-marked 3'-UTR of C/EBPβ gene was demonstrated as a strong enhancer element by luciferase assay. Our results indicate that histone modifications are gene-specific at adipogenic regulator genes, and they play distinct roles in regulating the transcriptional network during adipogenesis.

  16. A PSHaver for centromeric histones.

    Science.gov (United States)

    Folco, H Diego; Desai, Arshad

    2010-11-12

    In this issue of Molecular Cell, Hewawasam et al. (2010) and Ranjitkar et al. (2010) identify and characterize Psh1, an E3 ubiquitin ligase that specifically targets the centromeric histone Cse4 in budding yeast and limits its misincorporation at noncentromeric regions. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Drug Addiction and Histone Code Alterations.

    Science.gov (United States)

    Kim, Hee-Dae; Call, Tanessa; Magazu, Samantha; Ferguson, Deveroux

    2017-01-01

    Acute and prolonged exposure to drugs of abuse induces changes in gene expression, synaptic function, and neural plasticity in brain regions involved in reward. Numerous genes are involved in this process, and persistent changes in gene expression coincide with epigenetic histone modifications and DNA methylation. Histone modifications are attractive regulatory mechanisms, which can encode complex environmental signals in the genome of postmitotic cells, like neurons. Recently, it has been demonstrated that specific histone modifications are involved in addiction-related gene regulatory mechanisms, by a diverse set of histone-modifying enzymes and readers. These histone modifiers and readers may prove to be valuable pharmacological targets for effective treatments for drug addiction.

  18. Estimating tail probabilities

    Energy Technology Data Exchange (ETDEWEB)

    Carr, D.B.; Tolley, H.D.

    1982-12-01

    This paper investigates procedures for univariate nonparametric estimation of tail probabilities. Extrapolated values for tail probabilities beyond the data are also obtained based on the shape of the density in the tail. Several estimators which use exponential weighting are described. These are compared in a Monte Carlo study to nonweighted estimators, to the empirical cdf, to an integrated kernel, to a Fourier series estimate, to a penalized likelihood estimate and a maximum likelihood estimate. Selected weighted estimators are shown to compare favorably to many of these standard estimators for the sampling distributions investigated.

  19. Effects of Nickel, Chromate, and Arsenite on Histone 3 Lysine Methylation

    OpenAIRE

    Zhou, Xue; Li, Qin; Arita, Adriana; Sun, Hong; Costa, Max

    2009-01-01

    Occupational exposure to nickel(Ni), chromium(Cr), and arsenic(As) containing compounds has been associated with lung cancer and other adverse health effects. Their carcinogenic properties may be attributable in part, to activation and/or repression of gene expression induced by changes in the DNA methylation status and histone tail post-translational modifications. Here we show that individual treatment with nickel, chromate, and arsenite all affect the gene activating mark H3K4 methylation....

  20. Identification and Interrogation of Combinatorial Histone Modifications

    Directory of Open Access Journals (Sweden)

    Kelly R Karch

    2013-12-01

    Full Text Available Histone proteins are dynamically modified to mediate a variety of cellular processes including gene transcription, DNA damage repair, and apoptosis. Regulation of these processes occurs through the recruitment of non-histone proteins to chromatin by specific combinations of histone post-translational modifications (PTMs. Mass spectrometry has emerged as an essential tool to discover and quantify histone PTMs both within and between samples in an unbiased manner. Developments in mass spectrometry that allow for characterization of large histone peptides or intact protein has made it possible to determine which modifications occur simultaneously on a single histone polypeptide. A variety of techniques from biochemistry, biophysics, and chemical biology have been employed to determine the biological relevance of discovered combinatorial codes. This review first describes advancements in the field of mass spectrometry that have facilitated histone PTM analysis and then covers notable approaches to probe the biological relevance of these modifications in their nucleosomal context.

  1. Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2 in human oral cancer cell line.

    Directory of Open Access Journals (Sweden)

    Daisuke Yamamoto

    2010-09-01

    Full Text Available Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM, which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails.Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2. Protein level of DNA methyltransferase 3B (DNMT3B and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant.OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down-regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair.

  2. Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2) in human oral cancer cell line.

    Science.gov (United States)

    Yamamoto, Daisuke; Shima, Kaori; Matsuo, Kou; Nishioka, Takashi; Chen, Chang Yan; Hu, Guo-Fu; Sasaki, Akira; Tsuji, Takanori

    2010-09-03

    Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ) in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM), which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails. Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI) method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2). Protein level of DNA methyltransferase 3B (DNMT3B) and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant. OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down-regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair.

  3. Tail posture predicts tail damage among weaned piglets

    NARCIS (Netherlands)

    Zonderland, J.J.; Riel, van J.W.; Bracke, M.B.M.; Kemp, B.; Hartog, den L.A.; Spoolder, H.A.M.

    2009-01-01

    Tail biting in pigs is a widespread behavioural vice with significant animal welfare and economic consequences. All too often, tail biting is not diagnosed nor dealt with until tail damage is present. To effectively reduce the negative effects of tail biting, it must be diagnosed in an early stage.

  4. Reported tailings dam failures

    Energy Technology Data Exchange (ETDEWEB)

    Rico, M. [CSIC - Instituto Pirenaico de Ecologia, Zaragoza (Spain)], E-mail: mayterico@ipe.csic.es; Benito, G. [CSIC - Centro de Ciencias Medioambientales, Madrid (Spain); Salgueiro, A.R. [CERENA - Centro de Recursos Naturais e Ambiente of IST, Lisboa (Portugal); Diez-Herrero, A. [Geological Hazards Unit, Spanish Geological Survey (IGME), Madrid (Spain); Pereira, H.G. [CERENA - Centro de Recursos Naturais e Ambiente of IST, Lisboa (Portugal)

    2008-04-01

    A detailed search and re-evaluation of the known historical cases of tailings dam failure was carried out. A corpus of 147 cases of worldwide tailings dam disasters, from which 26 located in Europe, was compiled in a database. This contains six sections, including dam location, its physical and constructive characteristics, actual and putative failure cause, sludge hydrodynamics, socio-economical consequences and environmental impacts. Europe ranks in second place in reported accidents (18%), more than one third of them in dams 10-20 m high. In Europe, the most common cause of failure is related to unusual rain, whereas there is a lack of occurrences associated with seismic liquefaction, which is the second cause of tailings dam breakage elsewhere in the world. Moreover, over 90% of incidents occurred in active mines, and only 10% refer to abandoned ponds. The results reached by this preliminary analysis show an urgent need for EU regulations regarding technical standards of tailings disposal.

  5. Inequalities between hypergeometric tails

    Directory of Open Access Journals (Sweden)

    Mary C. Phipps

    2003-01-01

    Full Text Available A special inequality between the tail probabilities of certain related hypergeometrics was shown by Seneta and Phipps [19] to suggest useful ‘quasi-exact’ alternatives to Fisher's [5] Exact Test. With this result as motivation, two inequalities of Hájek and Havránek [6] are investigated in this paper and are generalised to produce inequalities in the form required. A parallel inequality in binomial tail probabilities is also established.

  6. A PHD in histone language

    Science.gov (United States)

    Chandrika, Nulu Naga Prafulla; Sundaravelpandian, Kalaipandian; Schmidt, Wolfgang

    2013-01-01

    Post-translational modifications of core histones are important for various DNA-templated processes such as transcription and repair. We recently reported that the ALFIN LIKE 6 (AL6) gene, identified in a forward genetic screen, is critical for phosphate deficiency-induced root hair formation and several other processes associated with the regulation of cellular phosphate homeostasis. AL6 contains a Plant Homeo Domain (PHD) finger that can bind to trimethylated lysine 4 of histone H3 (H3K4me3). Homozygous mutants defective in AL6 expression form very short root hairs under phosphate-deficient conditions, presumably caused by altered expression of putative primary and secondary down-stream targets of AL6. In this Addendum, we speculate about possible roles of AL6, H3K4 trimethylation and other chromatin modifications in the adaptation of plants to low phosphate availability. PMID:23531693

  7. Distribution of introns in fungal histone genes.

    Directory of Open Access Journals (Sweden)

    Choong-Soo Yun

    Full Text Available Saccharomycotina and Taphrinomycotina lack intron in their histone genes, except for an intron in one of histone H4 genes of Yarrowia lipolytica. On the other hand, Basidiomycota and Perizomycotina have introns in their histone genes. We compared the distributions of 81, 47, 79, and 98 introns in the fungal histone H2A, H2B, H3, and H4 genes, respectively. Based on the multiple alignments of the amino acid sequences of histones, we identified 19, 13, 31, and 22 intron insertion sites in the histone H2A, H2B, H3, and H4 genes, respectively. Surprisingly only one hot spot of introns in the histone H2A gene is shared between Basidiomycota and Perizomycotina, suggesting that most of introns of Basidiomycota and Perizomycotina were acquired independently. Our findings suggest that the common ancestor of Ascomycota and Basidiomycota maybe had a few introns in the histone genes. In the course of fungal evolution, Saccharomycotina and Taphrinomycotina lost the histone introns; Basidiomycota and Perizomycotina acquired other introns independently. In addition, most of the introns have sequence similarity among introns of phylogenetically close species, strongly suggesting that horizontal intron transfer events between phylogenetically distant species have not occurred recently in the fungal histone genes.

  8. Distribution of introns in fungal histone genes.

    Science.gov (United States)

    Yun, Choong-Soo; Nishida, Hiromi

    2011-01-27

    Saccharomycotina and Taphrinomycotina lack intron in their histone genes, except for an intron in one of histone H4 genes of Yarrowia lipolytica. On the other hand, Basidiomycota and Perizomycotina have introns in their histone genes. We compared the distributions of 81, 47, 79, and 98 introns in the fungal histone H2A, H2B, H3, and H4 genes, respectively. Based on the multiple alignments of the amino acid sequences of histones, we identified 19, 13, 31, and 22 intron insertion sites in the histone H2A, H2B, H3, and H4 genes, respectively. Surprisingly only one hot spot of introns in the histone H2A gene is shared between Basidiomycota and Perizomycotina, suggesting that most of introns of Basidiomycota and Perizomycotina were acquired independently. Our findings suggest that the common ancestor of Ascomycota and Basidiomycota maybe had a few introns in the histone genes. In the course of fungal evolution, Saccharomycotina and Taphrinomycotina lost the histone introns; Basidiomycota and Perizomycotina acquired other introns independently. In addition, most of the introns have sequence similarity among introns of phylogenetically close species, strongly suggesting that horizontal intron transfer events between phylogenetically distant species have not occurred recently in the fungal histone genes.

  9. Histone H1 Differentially Inhibits DNA Bending by Reduced and Oxidized HMGB1 Protein.

    Directory of Open Access Journals (Sweden)

    Michal Štros

    Full Text Available HMGB1 protein and linker histone H1 have overlapping binding sites in the nucleosome. HMGB1 has been implicated in many DNA-dependent processes in chromatin involving binding of specific proteins, including transcription factors, to DNA sites pre-bent by HMGB1. HMGB1 can also act as an extracellular signaling molecule by promoting inflammation, tumor growth a metastasis. Many of the intra- and extracellular functions of HMGB1 depend on redox-sensitive cysteine residues of the protein. Here we report that mild oxidization of HMGB1 (and much less mutation of cysteines involved in disulphide bond formation can severely compromise the functioning of the protein as a DNA chaperone by inhibiting its ability to unwind or bend DNA. Histone H1 (via the highly basic C-terminal domain significantly inhibits DNA bending by the full-length HMGB1, and the inhibition is further enhanced upon oxidization of HMGB1. Interestingly, DNA bending by HMGB1 lacking the acidic C-tail (HMGB1ΔC is much less affected by histone H1, but oxidization rendered DNA bending by HMGB1ΔC and HMGB1 equally prone for inhibition by histone H1. Possible consequences of histone H1-mediated inhibition of DNA bending by HMGB1 of different redox state for the functioning of chromatin are discussed.

  10. Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density.

    Directory of Open Access Journals (Sweden)

    Clint J Winkler

    2010-04-01

    Full Text Available Groucho (Gro is a Drosophila melanogaster transcriptional corepressor that directly interacts with the histone deacetylase Rpd3. Although previous studies suggest that this interaction is required for repression of Gro-responsive reporters in cultured cells, the in vivo significance of this interaction and the mechanism by which it leads to repression remain largely unexplored. In this study, we show that Gro is partially dependent on Rpd3 for repression, supporting the idea that Rpd3-mediated repression is one mode of Gro-mediated repression. We demonstrate that Gro colocalizes with Rpd3 to the chromatin of a target gene and that this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. Gro overexpression leads to wing patterning defects and ectopic repression in the wing disc of transcription directed by the vestigial quadrant enhancer. These effects are reversed by the histone deacetylase inhibitors TSA and HC-Toxin and by the reduction of Rpd3 gene dosage. Furthermore, repression of the vestigial quadrant enhancer is accompanied by a Gro-mediated increase in nucleosome density, an effect that is reversed by histone deacetylase inhibitors. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.

  11. Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density.

    Science.gov (United States)

    Winkler, Clint J; Ponce, Alberto; Courey, Albert J

    2010-04-13

    Groucho (Gro) is a Drosophila melanogaster transcriptional corepressor that directly interacts with the histone deacetylase Rpd3. Although previous studies suggest that this interaction is required for repression of Gro-responsive reporters in cultured cells, the in vivo significance of this interaction and the mechanism by which it leads to repression remain largely unexplored. In this study, we show that Gro is partially dependent on Rpd3 for repression, supporting the idea that Rpd3-mediated repression is one mode of Gro-mediated repression. We demonstrate that Gro colocalizes with Rpd3 to the chromatin of a target gene and that this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. Gro overexpression leads to wing patterning defects and ectopic repression in the wing disc of transcription directed by the vestigial quadrant enhancer. These effects are reversed by the histone deacetylase inhibitors TSA and HC-Toxin and by the reduction of Rpd3 gene dosage. Furthermore, repression of the vestigial quadrant enhancer is accompanied by a Gro-mediated increase in nucleosome density, an effect that is reversed by histone deacetylase inhibitors. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.

  12. Phylogenomics of unusual histone H2A Variants in Bdelloid rotifers.

    Science.gov (United States)

    Van Doninck, Karine; Mandigo, Morgan L; Hur, Jae H; Wang, Peter; Guglielmini, Julien; Milinkovitch, Michel C; Lane, William S; Meselson, Matthew

    2009-03-01

    Rotifers of Class Bdelloidea are remarkable in having evolved for millions of years, apparently without males and meiosis. In addition, they are unusually resistant to desiccation and ionizing radiation and are able to repair hundreds of radiation-induced DNA double-strand breaks per genome with little effect on viability or reproduction. Because specific histone H2A variants are involved in DSB repair and certain meiotic processes in other eukaryotes, we investigated the histone H2A genes and proteins of two bdelloid species. Genomic libraries were built and probed to identify histone H2A genes in Adineta vaga and Philodina roseola, species representing two different bdelloid families. The expressed H2A proteins were visualized on SDS-PAGE gels and identified by tandem mass spectrometry. We find that neither the core histone H2A, present in nearly all other eukaryotes, nor the H2AX variant, a ubiquitous component of the eukaryotic DSB repair machinery, are present in bdelloid rotifers. Instead, they are replaced by unusual histone H2A variants of higher mass. In contrast, a species of rotifer belonging to the facultatively sexual, desiccation- and radiation-intolerant sister class of bdelloid rotifers, the monogononts, contains a canonical core histone H2A and appears to lack the bdelloid H2A variant genes. Applying phylogenetic tools, we demonstrate that the bdelloid-specific H2A variants arose as distinct lineages from canonical H2A separate from those leading to the H2AX and H2AZ variants. The replacement of core H2A and H2AX in bdelloid rotifers by previously uncharacterized H2A variants with extended carboxy-terminal tails is further evidence for evolutionary diversity within this class of histone H2A genes and may represent adaptation to unusual features specific to bdelloid rotifers.

  13. Biochemical profiling of histone binding selectivity of the yeast bromodomain family.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    2010-01-01

    Full Text Available It has been shown that molecular interactions between site-specific chemical modifications such as acetylation and methylation on DNA-packing histones and conserved structural modules present in transcriptional proteins are closely associated with chromatin structural changes and gene activation. Unlike methyl-lysine that can interact with different protein modules including chromodomains, Tudor and MBT domains, as well as PHD fingers, acetyl-lysine (Kac is known thus far to be recognized only by bromodomains. While histone lysine acetylation plays a crucial role in regulation of chromatin-mediated gene transcription, a high degree of sequence variation of the acetyl-lysine binding site in the bromodomains has limited our understanding of histone binding selectivity of the bromodomain family. Here, we report a systematic family-wide analysis of 14 yeast bromodomains binding to 32 lysine-acetylated peptides derived from known major acetylation sites in four core histones that are conserved in eukaryotes.The histone binding selectivity of purified recombinant yeast bromodomains was assessed by using the native core histones in an overlay assay, as well as N-terminally biotinylated lysine-acetylated histone peptides spotted on streptavidin-coated nitrocellulose membrane in a dot blot assay. NMR binding analysis further validated the interactions between histones and selected bromodomain. Structural models of all yeast bromodomains were built using comparative modeling to provide insights into the molecular basis of their histone binding selectivity.Our study reveals that while not all members of the bromodomain family are privileged to interact with acetylated-lysine, identifiable sequence features from those that bind histone emerge. These include an asparagine residue at the C-terminus of the third helix in the 4-helix bundle, negatively charged residues around the ZA loop, and preponderance of aromatic amino acid residues in the binding pocket

  14. Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8

    DEFF Research Database (Denmark)

    Dorosz, Jerzy; Olsen, Lars; Seger, Signe Teuber

    2017-01-01

    The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain...... and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8...... in biochemical assays. The inhibitor has significantly lower affinity towards KDM2 enzymes (the phylogenetically closest subfamily), and to KDM3 and KDM6 subfamilies. Selectivity is only marginal towards an enzyme from the KDM4 family, which shares histone tail specificity with PHF8. It is a substrate of KDM5B...

  15. Sensitive and Precise Characterization of Combinatorial Histone Modifications by Selective Derivatization Coupled with RPLC-EThcD-MS/MS.

    Science.gov (United States)

    Liao, Rijing; Zheng, Dan; Nie, Aiying; Zhou, Shaolian; Deng, Haibing; Gao, Yuan; Yang, Pengyuan; Yu, Yanyan; Tan, Lin; Qi, Wei; Wu, Jiaxi; Li, En; Yi, Wei

    2017-02-03

    Deciphering the combinatorial histone codes has been a long-standing interest in the epigenetics field, which requires the reliable and robust characterization of the post-translational modifications (PTMs) coexisting on histones. To this end, weak cation exchange hydrophilic interaction liquid chromatography is commonly used in middle-down liquid chromatography-mass spectrometry approaches for online separation of variously modified histone peptides. Here we provide a novel strategy that combines the selective histone peptide derivatization using N-hydroxysuccinimide propionate ester with reversed-phase liquid chromatography (RPLC) for the robust, sensitive, and reliable characterization of combinatorial histone PTMs. Derivatization amplifies the subtle physical differences between similarly modified histone peptides, thereby allowing baseline separation of these peptides by standard RPLC. Also, the sensitivity of MS is enhanced greatly by derivatization due to the increased peptide hydrophobicity and concentrated charge-state envelope during electrospray ionization. Furthermore, we systematically optimized the dual electron transfer and higher energy collision dissociation and achieved near-complete peptide sequence coverage in MS/MS spectra, allowing highly precise and reliable PTM identification. Using this method, we identified 311 and 293 combinations of histone H3 PTMs from the lymphoma cells Karpas-422 with/without drug treatment, confirming the advantages of our method in serving as a platform for profiling combinatorial histone PTMs.

  16. Histone Acetylation in Fungal Pathogens of Plants

    Directory of Open Access Journals (Sweden)

    Junhyun Jeon

    2014-03-01

    Full Text Available Acetylation of histone lysine residues occurs in different organisms ranging from yeast to plants and mammals for the regulation of diverse cellular processes. With the identification of enzymes that create or reverse this modification, our understanding on histone acetylation has expanded at an amazing pace during the last two decades. In fungal pathogens of plants, however, the importance of such modification has only just begun to be appreciated in the recent years and there is a dearth of information on how histone acetylation is implicated in fungal pathogenesis. This review covers the current status of research related to histone acetylation in plant pathogenic fungi and considers relevant findings in the interaction between fungal pathogens and host plants. We first describe the families of histone acetyltransferases and deacetylases. Then we provide the cases where histone acetylation was investigated in the context of fungal pathogenesis. Finally, future directions and perspectives in epigenetics of fungal pathogenesis are discussed.

  17. Dynamic changes of histone H3 marks during Caenorhabditis elegans lifecycle revealed by middle-down proteomics.

    Science.gov (United States)

    Sidoli, Simone; Vandamme, Julien; Salcini, Anna Elisabetta; Jensen, Ole N

    2016-02-01

    We applied a middle-down proteomics strategy for large-scale protein analysis during in vivo development of Caenorhabditis elegans. We characterized PTMs on histone H3 N-terminal tails at eight time points during the C. elegans lifecycle, including embryo, larval stages (L1-L4), dauer, and L1/L4 postdauer. Histones were analyzed by our optimized middle-down protein sequencing platform using high mass accuracy MS/MS. This allows quantification of intact histone tails and detailed characterization of distinct histone tails carrying cooccurring PTMs. We measured temporally distinct combinatorial PTM profiles during C. elegans development. We show that the doubly modified form H3K23me3K27me3, which is rare or nonexistent in mammals, is the most abundant PTM in all stages of C. elegans lifecycle. The abundance of H3K23me3 increased during development and it was mutually exclusive of the active marks H3K18ac, R26me1, and R40me1, suggesting a role for H3K23me3 in silent chromatin. We observed distinct PTM profiles for normal L1 larvae and for L1-postdauer larvae, or L4 and L4 postdauer, suggesting that histone PTMs mediate an epigenetic memory that is transmitted during dauer formation. Collectively, our data describe the dynamics of histone H3 combinatorial code during C. elegans lifecycle and demonstrate the feasibility of using middle-down proteomics to study in vivo development of multicellular organisms. All MS data have been deposited in the ProteomeXchange with identifier PXD002525 (http://proteomecentral.proteomexchange.org/dataset/PXD002525). © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Basic nuclear processes affected by histone acetyltransferases and histone deacetylase inhibitors

    NARCIS (Netherlands)

    Legartová, Soňa; Stixová, Lenka; Strnad, Hynek; Kozubek, Stanislav; Martinet, Nadine; Dekker, Frank J; Franek, Michal; Bártová, Eva

    AIM: The optimal balance between histone acetylation and deacetylation is important for proper gene function. Therefore, we addressed how inhibitors of histone-modifying enzymes can modulate nuclear events, including replication, transcription, splicing and DNA repair. MATERIALS & METHODS: Changes

  19. Histone displacement during nucleotide excision repair

    DEFF Research Database (Denmark)

    Dinant, C.; Bartek, J.; Bekker-Jensen, S.

    2012-01-01

    chromatin. The condensed nature of chromatin inhibits many DNA metabolizing activities, including NER. In order to promote efficient repair, detection of a lesion not only has to activate the NER pathway but also chromatin remodeling. In general, such remodeling is thought on the one hand to precede NER...... of histone variants and histone displacement (including nucleosome sliding). Here we review current knowledge, and speculate about current unknowns, regarding those chromatin remodeling activities that physically displace histones before, during and after NER....

  20. Peptide microarrays to interrogate the "histone code".

    Science.gov (United States)

    Rothbart, Scott B; Krajewski, Krzysztof; Strahl, Brian D; Fuchs, Stephen M

    2012-01-01

    Histone posttranslational modifications (PTMs) play a pivotal role in regulating the dynamics and function of chromatin. Supported by an increasing body of literature, histone PTMs such as methylation and acetylation function together in the context of a "histone code," which is read, or interpreted, by effector proteins that then drive a functional output in chromatin (e.g., gene transcription). A growing number of domains that interact with histones and/or their PTMs have been identified. While significant advances have been made in our understanding of how these domains interact with histones, a wide number of putative histone-binding motifs have yet to be characterized, and undoubtedly, novel domains will continue to be discovered. In this chapter, we provide a detailed method for the construction of combinatorially modified histone peptides, microarray fabrication using these peptides, and methods to characterize the interaction of effector proteins, antibodies, and the substrate specificity of histone-modifying enzymes. We discuss these methods in the context of other available technologies and provide a user-friendly approach to enable the exploration of histone-protein-enzyme interactions and function. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Injurious tail biting in pigs

    DEFF Research Database (Denmark)

    D'Eath, R.B.; Amott, G.; Turner, S. P.

    2014-01-01

    Tail biting is a serious animal welfare and economic problem in pig production. Tail docking, which reduces but does not eliminate tail biting, remains widespread. However, in the EU tail docking may not be used routinely, and some ‘alternative’ forms of pig production and certain countries do...... not allow tail docking at all. Against this background, using a novel approach focusing on research where tail injuries were quantified, we review the measures that can be used to control tail biting in pigs without tail docking. Using this strict criterion, there was good evidence that manipulable...... substrates and feeder space affect damaging tail biting. Only epidemiological evidence was available for effects of temperature and season, and the effect of stocking density was unclear. Studies suggest that group size has little effect, and the effects of nutrition, disease and breed require further...

  2. Interactions of Histone Acetyltransferase p300 with the Nuclear Proteins Histone and HMGB1, As Revealed by Single Molecule Atomic Force Spectroscopy.

    Science.gov (United States)

    Banerjee, S; Rakshit, T; Sett, S; Mukhopadhyay, R

    2015-10-22

    One of the important properties of the transcriptional coactivator p300 is histone acetyltransferase (HAT) activity that enables p300 to influence chromatin action via histone modulation. p300 can exert its HAT action upon the other nuclear proteins too--one notable example being the transcription-factor-like protein HMGB1, which functions also as a cytokine, and whose accumulation in the cytoplasm, as a response to tissue damage, is triggered by its acetylation. Hitherto, no information on the structure and stability of the complexes between full-length p300 (p300FL) (300 kDa) and the histone/HMGB1 proteins are available, probably due to the presence of unstructured regions within p300FL that makes it difficult to be crystallized. Herein, we have adopted the high-resolution atomic force microscopy (AFM) approach, which allows molecularly resolved three-dimensional contour mapping of a protein molecule of any size and structure. From the off-rate and activation barrier values, obtained using single molecule dynamic force spectroscopy, the biochemical proposition of preferential binding of p300FL to histone H3, compared to the octameric histone, can be validated. Importantly, from the energy landscape of the dissociation events, a model for the p300-histone and the p300-HMGB1 dynamic complexes that HAT forms, can be proposed. The lower unbinding forces of the complexes observed in acetylating conditions, compared to those observed in non-acetylating conditions, indicate that upon acetylation, p300 tends to weakly associate, probably as an outcome of charge alterations on the histone/HMGB1 surface and/or acetylation-induced conformational changes. To our knowledge, for the first time, a single molecule level treatment of the interactions of HAT, where the full-length protein is considered, is being reported.

  3. HAT2 mediates histone H4K4 acetylation and affects micrococcal nuclease sensitivity of chromatin in Leishmania donovani.

    Directory of Open Access Journals (Sweden)

    Pravin K Jha

    Full Text Available Histone post-translational modifications (PTMs such as acetylation and methylation are known to affect chromatin higher order structures. Primary targets of these modifications include basic residues present at N-terminus tail region of core histones. Four histone acetyltransferase (HAT genes have been identified in trypanosomatids. HAT1, HAT3 and HAT4 of Leishmania donovani have been partially characterized. However, there is no report about HAT2 of Leishmania donovani. Lysine residues present on the N-terminal tail of Leishmania donovani histone H4 are conserved in other trypanosomatids and humans. PTMs of lysines modulate various functions at chromatin level. The four histone acetyltransferases encoded in Leishmania genome were over-expressed to analyse their functional activity. All four HATs were found actively acetylating core histones H3/H4. Similar to L. donovani HAT3 and HAT4, HAT2 was found to be a member of MYST family protein and have SAS2 type domain. Over-expression of HAT2 significantly increases acetylation of H4K4. To analyse the effect of HAT2 over-expression on chromatin accessibility, micrococcal nuclease digestion assay was performed. MNase digestion resulted in a higher proportion of the mononucleosomes and dinucleosomes in HAT2 over-expressing cells as compared to WT L. donovani cells. Acetylation of lysine-4 neutralizes the amino terminal region of histone H4. This weakens its interaction with neighbouring nucleosomes and the linker DNA. HAT2 over-expression in L. donovani resulted in highly accessible chromatin suggesting chromatin decondensation. HAT2 may have an important role to play in global regulation of transcription in L. donovani. Better understanding of these epigenetic determinants of parasite would help in designing novel therapeutic strategies.

  4. Telling tails: selective pressures acting on investment in lizard tails.

    Science.gov (United States)

    Fleming, Patricia A; Valentine, Leonie E; Bateman, Philip W

    2013-01-01

    Caudal autotomy is a common defense mechanism in lizards, where the animal may lose part or all of its tail to escape entrapment. Lizards show an immense variety in the degree of investment in a tail (i.e., length) across species, with tails of some species up to three or four times body length (snout-vent length [SVL]). Additionally, body size and form also vary dramatically, including variation in leg development and robustness and length of the body and tail. Autotomy is therefore likely to have fundamentally different effects on the overall body form and function in different species, which may be reflected directly in the incidence of lost/regenerating tails within populations or, over a longer period, in terms of relative tail length for different species. We recorded data (literature, museum specimens, field data) for relative tail length (n=350 species) and the incidence of lost/regenerating tails (n=246 species). We compared these (taking phylogeny into account) with intrinsic factors that have been proposed to influence selective pressures acting on caudal autotomy, including body form (robustness, body length, leg development, and tail specialization) and ecology (foraging behavior, physical and temporal niches), in an attempt to identify patterns that might reflect adaptive responses to these different factors. More gracile species have relatively longer tails (all 350 spp., P tails (P tails for nocturnal lizards (all 246 spp., P tail may be due to locomotor mechanics, although the patterns observed are also largely consistent with predictions based on predation pressure.

  5. Importance of electrostatic interactions in the association of intrinsically disordered histone chaperone Chz1 and histone H2A.Z-H2B.

    Directory of Open Access Journals (Sweden)

    Xiakun Chu

    Full Text Available Histone chaperones facilitate assembly and disassembly of nucleosomes. Understanding the process of how histone chaperones associate and dissociate from the histones can help clarify their roles in chromosome metabolism. Some histone chaperones are intrinsically disordered proteins (IDPs. Recent studies of IDPs revealed that the recognition of the biomolecules is realized by the flexibility and dynamics, challenging the century-old structure-function paradigm. Here we investigate the binding between intrinsically disordered chaperone Chz1 and histone variant H2A.Z-H2B by developing a structure-based coarse-grained model, in which Debye-Hückel model is implemented for describing electrostatic interactions due to highly charged characteristic of Chz1 and H2A.Z-H2B. We find that major structural changes of Chz1 only occur after the rate-limiting electrostatic dominant transition state and Chz1 undergoes folding coupled binding through two parallel pathways. Interestingly, although the electrostatic interactions stabilize bound complex and facilitate the recognition at first stage, the rate for formation of the complex is not always accelerated due to slow escape of conformations with non-native electrostatic interactions at low salt concentrations. Our studies provide an ionic-strength-controlled binding/folding mechanism, leading to a cooperative mechanism of "local collapse or trapping" and "fly-casting" together and a new understanding of the roles of electrostatic interactions in IDPs' binding.

  6. Double strand break repair functions of histone H2AX

    Energy Technology Data Exchange (ETDEWEB)

    Scully, Ralph, E-mail: rscully@bidmc.harvard.edu; Xie, Anyong

    2013-10-15

    Chromosomal double strand breaks provoke an extensive reaction in neighboring chromatin, characterized by phosphorylation of histone H2AX on serine 139 of its C-terminal tail (to form “γH2AX”). The γH2AX response contributes to the repair of double strand breaks encountered in a variety of different contexts, including those induced by ionizing radiation, physiologically programmed breaks that characterize normal immune cell development and the pathological exposure of DNA ends triggered by telomere dysfunction. γH2AX also participates in the evolutionarily conserved process of sister chromatid recombination, a homologous recombination pathway involved in the suppression of genomic instability during DNA replication and directly implicated in tumor suppression. At a biochemical level, the γH2AX response provides a compelling example of how the “histone code” is adapted to the regulation of double strand break repair. Here, we review progress in research aimed at understanding how γH2AX contributes to double strand break repair in mammalian cells.

  7. "Tails" of Linguistic Survival

    Science.gov (United States)

    Timmis, Ivor

    2010-01-01

    Given the relatively short history of computerized corpora of spoken language, it is not surprising that few diachronic studies have been done on the grammatical features recently highlighted by the analysis of such corpora. This article, however, does take a diachronic perspective on one such feature: the syntactic feature of "tails"…

  8. White-tailed deer

    Science.gov (United States)

    Paul E. Johns; John C. Kilgo

    2005-01-01

    from a public relations standpoint, the white-tailed deer (Odocileus virginiamus) is probably the most important wildlife species occurring on the Savannah River Site (SRS). The SRS deer herd has been the subject of more scientific investigations than any comparable deer population in the world, resulting in more than 125 published papers. Each year...

  9. Estimation of Jump Tails

    DEFF Research Database (Denmark)

    Bollerslev, Tim; Todorov, Victor

    We propose a new and flexible non-parametric framework for estimating the jump tails of Itô semimartingale processes. The approach is based on a relatively simple-to-implement set of estimating equations associated with the compensator for the jump measure, or its "intensity", that only utilizes...

  10. Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression*

    Science.gov (United States)

    Brocato, Jason; Fang, Lei; Chervona, Yana; Chen, Danqi; Kiok, Kathrin; Sun, Hong; Tseng, Hsiang-Chi; Xu, Dazhong; Shamy, Magdy; Jin, Chunyuan; Costa, Max

    2014-01-01

    The replication-dependent histone genes are the only metazoan genes whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3′-end. Instead, the histone mRNAs display a stem-loop structure at their 3′-end. Stem-loop-binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. Here we report that exposure to arsenic, a carcinogenic metal, decreased cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Notably, arsenic exposure dramatically increased polyadenylation of canonical histone H3.1 mRNA possibly through down-regulation of SLBP expression. The polyadenylated H3.1 mRNA induced by arsenic was not susceptible to normal degradation that occurs at the end of S phase, resulting in continued presence into mitosis, increased total H3.1 mRNA, and increased H3 protein levels. Excess expression of canonical histones have been shown to increase sensitivity to DNA damage as well as increase the frequency of missing chromosomes and induce genomic instability. Thus, polyadenylation of canonical histone mRNA following arsenic exposure may contribute to arsenic-induced carcinogenesis. PMID:25266719

  11. Drawbacks in the use of unconventional hydrophobic anhydrides for histone derivatization in bottom-up proteomics PTM analysis.

    Science.gov (United States)

    Sidoli, Simone; Yuan, Zuo-Fei; Lin, Shu; Karch, Kelly; Wang, Xiaoshi; Bhanu, Natarajan; Arnaudo, Anna M; Britton, Laura-Mae; Cao, Xing-Jun; Gonzales-Cope, Michelle; Han, Yumiao; Liu, Shichong; Molden, Rosalynn C; Wein, Samuel; Afjehi-Sadat, Leila; Garcia, Benjamin A

    2015-05-01

    MS-based proteomics has become the most utilized tool to characterize histone PTMs. Since histones are highly enriched in lysine and arginine residues, lysine derivatization has been developed to prevent the generation of short peptides (<6 residues) during trypsin digestion. One of the most adopted protocols applies propionic anhydride for derivatization. However, the propionyl group is not sufficiently hydrophobic to fully retain the shortest histone peptides in RP LC, and such procedure also hampers the discovery of natural propionylation events. In this work we tested 12 commercially available anhydrides, selected based on their safety and hydrophobicity. Performance was evaluated in terms of yield of the reaction, MS/MS fragmentation efficiency, and drift in retention time using the following samples: (i) a synthetic unmodified histone H3 tail, (ii) synthetic modified histone peptides, and (iii) a histone extract from cell lysate. Results highlighted that seven of the selected anhydrides increased peptide retention time as compared to propionic, and several anhydrides such as benzoic and valeric led to high MS/MS spectra quality. However, propionic anhydride derivatization still resulted, in our opinion, as the best protocol to achieve high MS sensitivity and even ionization efficiency among the analyzed peptides. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Ethanol precipitation analysis of thymus histone

    NARCIS (Netherlands)

    Bijvoet, P.

    1957-01-01

    An analytical ethanol precipitation technique, similar to 's salting-out procedure, was used for the characterisation of whole thymus histone and the products obtained by preparative ethanol fractionation. The analysis was carried out at —5° C and pH 6.5. Whole histone prepared according to et al.,

  13. Histone acetyl transferases as emerging drug targets

    NARCIS (Netherlands)

    Dekker, Frank J.; Haisma, Hidde J.

    2009-01-01

    Post-translational modifications, such as acetylation or phosphorylation, play a crucial role in the regulation of gene transcription in eukaryotes. Different subtypes of histone acetyl transferases (HATs) catalyze the acetylation of histones on specific lysine residues. A potential role of HATs in

  14. Histone modifications: Cycling with chromosomal replication

    DEFF Research Database (Denmark)

    Thon, Genevieve

    2008-01-01

    Histone modifications tend to be lost during chromosome duplication. Several recent studies suggest that the RNA interference pathway becomes active during the weakened transcriptional repression occurring at centromeres in S phase, resulting in the re-establishment of histone modifications that ...

  15. Histone gene complement, variant expression, and mRNA processing in a urochordate Oikopleura dioica that undergoes extensive polyploidization.

    Science.gov (United States)

    Chioda, Mariacristina; Eskeland, Ragnhild; Thompson, Eric M

    2002-12-01

    Considerable data exist on coding sequences of histones in a wide variety of organisms. Much more restricted information is available on total histone gene complement, gene organization, transcriptional regulation, and histone mRNA processing. In particular, there is a significant phylogenetic gap in information for the urochordates, a subphylum near the invertebrate-vertebrate transition. In this study, we show that the appendicularian Oikopleura dioica has a histone gene complement that is similar to that of humans, though its genome size is 40- to 50-fold smaller. At a total length of 3.5 kb, the H3, H4, H1, H2A, and H2B quintet cluster is the most compact described thus far, but despite very rapid early developmental cleavage cycles, no extensive tandem repeats of the cluster were present. The high degree of variation within each of the complements of O. dioica H2A and H2B subtypes resembled that found in plants as opposed to more closely related vertebrate and invertebrate species, and developmental stage-specific expression of different subtypes was observed. The linker histone H1 was present in relatively few copies per haploid genome and contained short N- and C-terminal tails, a feature similar to that of copepods but different from many standard model organisms. The 3'UTRs of the histone genes contained both the consensus stem-loop sequence and the polyadenylation signals but lacked the consensus histone downstream element that is involved in the processing of histone mRNAs in echinoderms and vertebrates. Two types of transcripts were found, i.e., those containing both the stem-loop and a polyA tail as well as those cleaved at the normal site just 3' of the stem-loop. The O. dioica data are an important addition to the limited number of eukaryotes for which sufficiently extensive information on histone gene complements is available. Increasingly, it appears that understanding the evolution of histone gene organization, transcriptional regulation, and m

  16. Preferential Phosphorylation on Old Histones during Early Mitosis in Human Cells.

    Science.gov (United States)

    Lin, Shu; Yuan, Zuo-Fei; Han, Yumiao; Marchione, Dylan M; Garcia, Benjamin A

    2016-07-15

    How histone post-translational modifications (PTMs) are inherited through the cell cycle remains poorly understood. Canonical histones are made in the S phase of the cell cycle. Combining mass spectrometry-based technologies and stable isotope labeling by amino acids in cell culture, we question the distribution of multiple histone PTMs on old versus new histones in synchronized human cells. We show that histone PTMs can be grouped into three categories according to their distributions. Most lysine mono-methylation and acetylation PTMs are either symmetrically distributed on old and new histones or are enriched on new histones. In contrast, most di- and tri-methylation PTMs are enriched on old histones, suggesting that the inheritance of different PTMs is regulated distinctly. Intriguingly, old and new histones are distinct in their phosphorylation status during early mitosis in the following three human cell types: HeLa, 293T, and human foreskin fibroblast cells. The mitotic hallmark H3S10ph is predominantly associated with old H3 at early mitosis and becomes symmetric with the progression of mitosis. This same distribution was observed with other mitotic phosphorylation marks, including H3T3/T6ph, H3.1/2S28ph, and H1.4S26ph but not S28/S31ph on the H3 variant H3.3. Although H3S10ph often associates with the neighboring Lys-9 di- or tri-methylations, they are not required for the asymmetric distribution of Ser-10 phosphorylation on the same H3 tail. Inhibition of the kinase Aurora B does not change the distribution despite significant reduction of H3S10ph levels. However, K9me2 abundance on the new H3 is significantly reduced after Aurora B inhibition, suggesting a cross-talk between H3S10ph and H3K9me2. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Histone variants in plant transcriptional regulation.

    Science.gov (United States)

    Jiang, Danhua; Berger, Frédéric

    2017-01-01

    Chromatin based organization of eukaryotic genome plays a profound role in regulating gene transcription. Nucleosomes form the basic subunits of chromatin by packaging DNA with histone proteins, impeding the access of DNA to transcription factors and RNA polymerases. Exchange of histone variants in nucleosomes alters the properties of nucleosomes and thus modulates DNA exposure during transcriptional regulation. Growing evidence indicates the important function of histone variants in programming transcription during developmental transitions and stress response. Here we review how histone variants and their deposition machineries regulate the nucleosome stability and dynamics, and discuss the link between histone variants and transcriptional regulation in plants. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Acetylated histone H3 increases nucleosome dissociation

    Science.gov (United States)

    Simon, Marek; Manohar, Mridula; Ottesen, Jennifer; Poirier, Michael

    2009-03-01

    Chromatin's basic unit structure is the nucleosome, i.e. genomic DNA wrapped around a particular class of proteins -- histones -- which due to their physical hindrance, block vital biological processes, such as DNA repair, DNA replication, and RNA transcription. Histone post-translational modifications, which are known to exist in vivo, are hypothesized to regulate these biological processes by directly altering DNA-histone interactions and thus nucleosome structure and stability. Using magnetic tweezers technique we studied the acetylation of histone H3 in the dyad region, i.e. at K115 and K122, on reconstituted arrays of nucleosomes under constant external force. Based on the measured increase in the probability of dissociation of modified nucleosomes, we infer that this double modification could facilitate histone chaperone mediated nucleosome disassembly in vivo.

  19. Tail autotomy, tail size, and locomotor performance in lizards.

    Science.gov (United States)

    McElroy, Eric J; Bergmann, Philip J

    2013-01-01

    The effect of tail autotomy on locomotor performance has been studied in a number of lizard species. Most of these studies (65%) show that tail autotomy has a negative effect on sprint speed, some studies (26%) show no effect of autotomy on sprint speed, and a few (9%) show a positive effect of autotomy on sprint speed. A variety of hypotheses have been proposed to explain the variation across these studies, but none has been tested. We synthesize these data using meta-analysis and then test whether any of four variables explain the variation in how tail autotomy impacts sprint speed: (1) differences in methodology in previous studies, (2) phylogeny, (3) relative tail size, and (4) habitat use. We find little evidence that methodology or habitat use influences how sprint speed changes following tail autotomy. Although the sampling is phylogenetically sparse, phylogeny appears to play a role, with skinks and iguanids showing fairly consistent decreases in speeds after autotomy and with lacertids and geckos showing large variation in how autotomy impacts speed. After removing two outlying species with unusually large and long tails (Takydromus sp.), we find a positive relationship between relative tail size and sprint speed change after autotomy. Lizards with larger tails exhibit a greater change in speed after tail loss. This finding suggests that future studies of tail autotomy and locomotor performance might profitably incorporate variation in tail size and that species-specific responses to autotomy need to be considered.

  20. Recurrent Gene Duplication Leads to Diverse Repertoires of Centromeric Histones in Drosophila Species.

    Science.gov (United States)

    Kursel, Lisa E; Malik, Harmit S

    2017-06-01

    Despite their essential role in the process of chromosome segregation in most eukaryotes, centromeric histones show remarkable evolutionary lability. Not only have they been lost in multiple insect lineages, but they have also undergone gene duplication in multiple plant lineages. Based on detailed study of a handful of model organisms including Drosophila melanogaster, centromeric histone duplication is considered to be rare in animals. Using a detailed phylogenomic study, we find that Cid, the centromeric histone gene, has undergone at least four independent gene duplications during Drosophila evolution. We find duplicate Cid genes in D. eugracilis (Cid2), in the montium species subgroup (Cid3, Cid4) and in the entire Drosophila subgenus (Cid5). We show that Cid3, Cid4, and Cid5 all localize to centromeres in their respective species. Some Cid duplicates are primarily expressed in the male germline. With rare exceptions, Cid duplicates have been strictly retained after birth, suggesting that they perform nonredundant centromeric functions, independent from the ancestral Cid. Indeed, each duplicate encodes a distinct N-terminal tail, which may provide the basis for distinct protein-protein interactions. Finally, we show some Cid duplicates evolve under positive selection whereas others do not. Taken together, our results support the hypothesis that Drosophila Cid duplicates have subfunctionalized. Thus, these gene duplications provide an unprecedented opportunity to dissect the multiple roles of centromeric histones. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  1. Histone deacetylases (HDACs and brain function

    Directory of Open Access Journals (Sweden)

    Claude-Henry Volmar

    2015-01-01

    Full Text Available Modulation of gene expression is a constant and necessary event for mammalian brain function. An important way of regulating gene expression is through the remodeling of chromatin, the complex of DNA, and histone proteins around which DNA wraps. The “histone code hypothesis” places histone post-translational modifications as a significant part of chromatin remodeling to regulate transcriptional activity. Acetylation of histones by histone acetyl transferases and deacetylation by histone deacetylases (HDACs at lysine residues are the most studied histone post-translational modifications in cognition and neuropsychiatric diseases. Here, we review the literature regarding the role of HDACs in brain function. Among the roles of HDACs in the brain, studies show that they participate in glial lineage development, learning and memory, neuropsychiatric diseases, and even rare neurologic diseases. Most HDACs can be targeted with small molecules. However, additional brain-penetrant specific inhibitors with high central nervous system exposure are needed to determine the cause-and-effect relationship between individual HDACs and brain-associated diseases.

  2. Histone demethylases in development and disease

    DEFF Research Database (Denmark)

    Pedersen, Marianne Terndrup; Helin, Kristian

    2010-01-01

    Histone modifications serve as regulatory marks that are instrumental for the control of transcription and chromatin architecture. Strict regulation of gene expression patterns is crucial during development and differentiation, where diverse cell types evolve from common predecessors. Since...... the first histone lysine demethylase was discovered in 2004, a number of demethylases have been identified and implicated in the control of gene expression programmes and cell fate decisions. Histone demethylases are now emerging as important players in developmental processes and have been linked to human...

  3. Metabolic labeling in middle-down proteomics allows for investigation of the dynamics of the histone code.

    Science.gov (United States)

    Sidoli, Simone; Lu, Congcong; Coradin, Mariel; Wang, Xiaoshi; Karch, Kelly R; Ruminowicz, Chrystian; Garcia, Benjamin A

    2017-07-06

    Middle-down mass spectrometry (MS), i.e., analysis of long (~50-60 aa) polypeptides, has become the method with the highest throughput and accuracy for the characterization of combinatorial histone posttranslational modifications (PTMs). The discovery of histone readers with multiple domains, and overall the cross talk of PTMs that decorate histone proteins, has revealed that histone marks have synergistic roles in modulating enzyme recruitment and subsequent chromatin activities. Here, we demonstrate that the middle-down MS strategy can be combined with metabolic labeling for enhanced quantification of histone proteins and their combinatorial PTMs in a dynamic manner. We used a nanoHPLC-MS/MS system consisting of hybrid weak cation exchange-hydrophilic interaction chromatography combined with high resolution MS and MS/MS with ETD fragmentation. After spectra identification, we filtered confident hits and quantified polypeptides using our in-house software isoScale. We first verified that middle-down MS can discriminate and differentially quantify unlabeled from heavy labeled histone N-terminal tails (heavy lysine and arginine residues). Results revealed no bias toward identifying and quantifying unlabeled versus heavy labeled tails, even if the heavy labeled peptides presented the typical skewed isotopic pattern typical of long protein sequences that hardly get 100% labeling. Next, we plated epithelial cells into a media with heavy methionine-(methyl-13CD3), the precursor of the methyl donor S-adenosylmethionine and stimulated epithelial to mesenchymal transition (EMT). We assessed that results were reproducible across biological replicates and with data obtained using the more widely adopted bottom-up MS strategy, i.e., analysis of short tryptic peptides. We found remarkable differences in the incorporation rate of methylations in non-confluent cells versus confluent cells. Moreover, we showed that H3K27me3 was a critical player during the EMT process, as a

  4. Post-translational modifications of linker histone H1 variants in mammals

    Science.gov (United States)

    Starkova, T. Yu; Polyanichko, A. M.; Artamonova, T. O.; Khodorkovskii, M. A.; Kostyleva, E. I.; Chikhirzhina, E. V.; Tomilin, A. N.

    2017-02-01

    The covalent modifications of the linker histone H1 and the core histones are thought to play an important role in the control of chromatin functioning. Histone H1 variants from K562 cell line (hH1), mouse (mH1) and calf (cH1) thymi were studied by matrix-activated laser desorption/ionization fourier transform ion cyclotron resonance mass-spectroscopy (MALDI-FT-ICR-MS). The proteomics analysis revealed novel post-translational modifications of the histone H1, such as meK34-mH1.4, meK35-cH1.1, meK35-mH1.1, meK75-hH1.2, meK75-hH1.3, acK26-hH1.4, acK26-hH1.3 and acK17-hH1.1. The comparison of the hH1, mH1 and cH1 proteins has demonstrated that the types and positions of the post-translational modifications of the globular domains of the H1.2-H1.4 variants are very conservative. However, the post-translational modifications of the N- and C-terminal tails of H1.2, H1.3 and H1.4 are different. The differences of post-translational modifications in the N- and C-terminal tails of H1.2, H1.3 and H1.4 likely lead to the differences in DNA-H1 and H1-protein interactions.

  5. Post-translational modifications of linker histone H1 variants in mammals.

    Science.gov (United States)

    Starkova, T Yu; Polyanichko, A M; Artamonova, T O; Khodorkovskii, M A; Kostyleva, E I; Chikhirzhina, E V; Tomilin, A N

    2017-02-16

    The covalent modifications of the linker histone H1 and the core histones are thought to play an important role in the control of chromatin functioning. Histone H1 variants from K562 cell line (hH1), mouse (mH1) and calf (cH1) thymi were studied by matrix-activated laser desorption/ionization fourier transform ion cyclotron resonance mass-spectroscopy (MALDI-FT-ICR-MS). The proteomics analysis revealed novel post-translational modifications of the histone H1, such as meK34-mH1.4, meK35-cH1.1, meK35-mH1.1, meK75-hH1.2, meK75-hH1.3, acK26-hH1.4, acK26-hH1.3 and acK17-hH1.1. The comparison of the hH1, mH1 and cH1 proteins has demonstrated that the types and positions of the post-translational modifications of the globular domains of the H1.2-H1.4 variants are very conservative. However, the post-translational modifications of the N- and C-terminal tails of H1.2, H1.3 and H1.4 are different. The differences of post-translational modifications in the N- and C-terminal tails of H1.2, H1.3 and H1.4 likely lead to the differences in DNA-H1 and H1-protein interactions.

  6. Molecular mechanisms and potential functions of histone demethylases

    DEFF Research Database (Denmark)

    Kooistra, Susanne Marije; Helin, Kristian

    2012-01-01

    Histone modifications are thought to regulate chromatin structure, transcription and other nuclear processes. Histone methylation was originally believed to be an irreversible modification that could only be removed by histone eviction or by dilution during DNA replication. However, the isolation...... of two families of enzymes that can demethylate histones has changed this notion. The biochemical activities of these histone demethylases towards specific Lys residues on histones, and in some cases non-histone substrates, have highlighted their importance in developmental control, cell-fate decisions...

  7. Function of histone deacetylase inhibitors in inflammation

    NARCIS (Netherlands)

    Grabiec, Aleksander M.; Tak, Paul P.; Reedquist, Kris A.

    2011-01-01

    Histone deacetylases (HDACs) display multi-faceted roles in coordinating the interaction of intracellular signaling pathways with chromatin remodeling and transcription factor function to finely specify gene alterations and maintenance of gene expression during cellular activation, proliferation,

  8. Molecular dynamics of histone H1

    National Research Council Canada - National Science Library

    Raghuram, Nikhil; Carrero, Gustavo; Thng, John; Hendzel, Michael J

    2009-01-01

    .... In this review, we focus on the wealth of information gathered on the molecular kinetics of histone H1 molecules using novel imaging techniques, such as fluorescence recovery after photobleaching...

  9. Detection of histone acetylation levels in the dorsal hippocampus reveals early tagging on specific residues of H2B and H4 histones in response to learning.

    Directory of Open Access Journals (Sweden)

    Olivier Bousiges

    Full Text Available The recent literature provides evidence that epigenetic mechanisms such as DNA methylation and histone modification are crucial to gene transcription linked to synaptic plasticity in the mammalian brain--notably in the hippocampus--and memory formation. We measured global histone acetylation levels in the rat hippocampus at an early stage of spatial or fear memory formation. We found that H3, H4 and H2B underwent differential acetylation at specific sites depending on whether rats had been exposed to the context of a task without having to learn or had to learn about a place or fear therein: H3K9K14 acetylation was mostly responsive to any experimental conditions compared to naive animals, whereas H2B N-terminus and H4K12 acetylations were mostly associated with memory for either spatial or fear learning. Altogether, these data suggest that behavior/experience-dependent changes differently regulate specific acetylation modifications of histones in the hippocampus, depending on whether a memory trace is established or not: tagging of H3K9K14 could be associated with perception/processing of testing-related manipulations and context, thereby enhancing chromatin accessibility, while tagging of H2B N-terminus tail and H4K12 could be more closely associated with the formation of memories requiring an engagement of the hippocampus.

  10. Cracking the survival code: autophagy-related histone modifications.

    Science.gov (United States)

    Füllgrabe, Jens; Heldring, Nina; Hermanson, Ola; Joseph, Bertrand

    2014-04-01

    Modifications of histones, the chief protein components of the chromatin, have emerged as critical regulators of life and death. While the "apoptotic histone code" came to light a few years ago, accumulating evidence indicates that autophagy, a cell survival pathway, is also heavily regulated by histone-modifying proteins. In this review we describe the emerging "autophagic histone code" and the role of histone modifications in the cellular life vs. death decision.

  11. A fluorescence resonance energy transfer-based method for histone methyltransferases

    DEFF Research Database (Denmark)

    Devkota, Kanchan; Lohse, Brian; Nyby Jakobsen, Camilla

    2015-01-01

    A simple dye–quencher fluorescence resonance energy transfer (FRET)-based assay for methyltransferases was developed and used to determine kinetic parameters and inhibitory activity at EHMT1 and EHMT2. Peptides mimicking the truncated histone H3 tail were functionalized in each end with a dye...... and a quencher, respectively. When lysine-9 residues in the peptides were methylated, they were protected from cleavage by endoproteinase–EndoLysC, whereas unmethylated peptides were cleaved, resulting in an increase in fluorescent intensity....

  12. Histone Lysine Methylation in Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Guang-dong Sun

    2014-01-01

    Full Text Available Diabetic nephropathy (DN belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called “metabolic memory.” The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN.

  13. Deciphering the histone code using mass spectrometry

    Science.gov (United States)

    Ueberheide, Beatrix M.; Mollah, Sahana

    2007-01-01

    During the past decade, studies surrounding chromatin research have grown exponentially. A major focus of chromatin biology is centered on understanding of how histone modifications alter chromatin structure at the molecular and mechanistic levels. Discoveries are being made at a rapid pace due to the advent of new and innovative techniques. Mass spectrometry has emerged as a powerful tool in the field of histone research due to its speed, sensitivity, and ease of use. This has resulted in the identification of a number of novel histone modification sites. In consequence, new roles in biological processes have been discovered and hypothetical models, such as the `histone code' have been reaffirmed or refined. One significant advantage to using mass spectrometric techniques is that the combinations of modifications on different sites can be determined which is crucial to deciphering the `histone code'. In this manuscript, the mass spectrometric approaches developed over the past decade for both qualitative and quantitative analysis of histone post-translational modifications (PTMs) are discussed.

  14. EnD-Seq and AppEnD: sequencing 3′ ends to identify nontemplated tails and degradation intermediates

    Science.gov (United States)

    Welch, Joshua D.; Slevin, Michael K.; Tatomer, Deirdre C.; Duronio, Robert J.

    2015-01-01

    Existing methods for detecting RNA intermediates resulting from exonuclease degradation are low-throughput and laborious. In addition, mapping the 3′ ends of RNA molecules to the genome after high-throughput sequencing is challenging, particularly if the 3′ ends contain post-transcriptional modifications. To address these problems, we developed EnD-Seq, a high-throughput sequencing protocol that preserves the 3′ end of RNA molecules, and AppEnD, a computational method for analyzing high-throughput sequencing data. Together these allow determination of the 3′ ends of RNA molecules, including nontemplated additions. Applying EnD-Seq and AppEnD to histone mRNAs revealed that a significant fraction of cytoplasmic histone mRNAs end in one or two uridines, which have replaced the 1–2 nt at the 3′ end of mature histone mRNA maintaining the length of the histone transcripts. Histone mRNAs in fly embryos and ovaries show the same pattern, but with different tail nucleotide compositions. We increase the sensitivity of EnD-Seq by using cDNA priming to specifically enrich low-abundance tails of known sequence composition allowing identification of degradation intermediates. In addition, we show the broad applicability of our computational approach by using AppEnD to gain insight into 3′ additions from diverse types of sequencing data, including data from small capped RNA sequencing and some alternative polyadenylation protocols. PMID:26015596

  15. Staphylococcus aureus protease: a probe of exposed, non-basic histone sequences in nucleosomes

    Energy Technology Data Exchange (ETDEWEB)

    Rill, R.L.; Oosterhof, D.K.

    1980-01-01

    The digestion of histones in chicken erythrocyte nucleosome cores and chromatin by Staphylococcus aureus protease was examined. This protease cleaves specifically at acidic residues and prefers glu-X bonds under the conditions used. Only 1 of 24 glutamic and 2 of 13 aspartic acids among all four core histones are located in basic, amino-terminal tails, hence staph. protease is a highly specific probe of exposed non-basic sequences. Staph. protease readily degraded H1, H5, and H3; moderately degraded H2b, and only slightly degraded H2a and H4 in nucleosomes and nucleosome cores. Electrophoresis of core histone fragments from limited digests showed that most glutamic acids were inaccessible, but at least five sites in non-basic sequences were readily cleaved. Tentative assignments of these fragments based on comparisons with products from limited digests of pure histones suggested that most accessible sites in nucleosome cores occur in H3. The most probable sites of H3 cutting are glutamic acids at positions 51, 60, 73, 94, and 97. At least one site in H2b, probably the equivalent of glu-105 in the calf H2b sequence, was accessible. No sites in H2a and H4 appeared highly accessible. H5 was readily cleaved at a site near the amino-terminus. These data substantiate the other evidence that non-basic core histone sequences are located primarily in the nucleosome interior, but that H3 binds to the ends of core DNA and thereby is partly exposed as the upper and lower surfaces of the disk-shaped core.

  16. Pattern of change in histone 3 lysine 9 acetylation and histone ...

    Indian Academy of Sciences (India)

    Pattern of change in histone 3 lysine 9 acetylation and histone deacetylases in development of zebrafish embryo. Yanning Li Junxia Wang Ying Xie Shufeng Liu Ye ... Wang1 Ying Xie1 Shufeng Liu1 Ye Tian1. Hebei Key Lab of Laboratory Animal, Hebei Medical University, Shijiazhuang 050017, People's Republic of China ...

  17. Replication stress interferes with histone recycling and predeposition marking of new histones

    DEFF Research Database (Denmark)

    Jasencakova, Zuzana; Scharf, Annette N D; Ask, Katrine

    2010-01-01

    To restore chromatin on new DNA during replication, recycling of histones evicted ahead of the fork is combined with new histone deposition. The Asf1 histone chaperone, which buffers excess histones under stress, is a key player in this process. Yet how histones handled by human Asf1 are modified...... remains unclear. Here we identify marks on histones H3-H4 bound to Asf1 and changes induced upon replication stress. In S phase, distinct cytosolic and nuclear Asf1b complexes show ubiquitous H4K5K12diAc and heterogeneous H3 marks, including K9me1, K14ac, K18ac, and K56ac. Upon acute replication arrest......, the predeposition mark H3K9me1 and modifications typical of chromatin accumulate in Asf1 complexes. In parallel, ssDNA is generated at replication sites, consistent with evicted histones being trapped with Asf1. During recovery, histones stored with Asf1 are rapidly used as replication resumes. This shows...

  18. Meiosis-Specific Loading of the Centromere-Specific Histone CENH3 in Arabidopsis thaliana

    Science.gov (United States)

    Ravi, Maruthachalam; Shibata, Fukashi; Ramahi, Joseph S.; Nagaki, Kiyotaka; Chen, Changbin; Murata, Minoru; Chan, Simon W. L.

    2011-01-01

    Centromere behavior is specialized in meiosis I, so that sister chromatids of homologous chromosomes are pulled toward the same side of the spindle (through kinetochore mono-orientation) and chromosome number is reduced. Factors required for mono-orientation have been identified in yeast. However, comparatively little is known about how meiotic centromere behavior is specialized in animals and plants that typically have large tandem repeat centromeres. Kinetochores are nucleated by the centromere-specific histone CENH3. Unlike conventional histone H3s, CENH3 is rapidly evolving, particularly in its N-terminal tail domain. Here we describe chimeric variants of CENH3 with alterations in the N-terminal tail that are specifically defective in meiosis. Arabidopsis thaliana cenh3 mutants expressing a GFP-tagged chimeric protein containing the H3 N-terminal tail and the CENH3 C-terminus (termed GFP-tailswap) are sterile because of random meiotic chromosome segregation. These defects result from the specific depletion of GFP-tailswap protein from meiotic kinetochores, which contrasts with its normal localization in mitotic cells. Loss of the GFP-tailswap CENH3 variant in meiosis affects recruitment of the essential kinetochore protein MIS12. Our findings suggest that CENH3 loading dynamics might be regulated differently in mitosis and meiosis. As further support for our hypothesis, we show that GFP-tailswap protein is recruited back to centromeres in a subset of pollen grains in GFP-tailswap once they resume haploid mitosis. Meiotic recruitment of the GFP-tailswap CENH3 variant is not restored by removal of the meiosis-specific cohesin subunit REC8. Our results reveal the existence of a specialized loading pathway for CENH3 during meiosis that is likely to involve the hypervariable N-terminal tail. Meiosis-specific CENH3 dynamics may play a role in modulating meiotic centromere behavior. PMID:21695238

  19. Mythical 'Tails of Lockwood'.

    Science.gov (United States)

    Nightingale, Sophie S; Al Shareef, Yasir R; Hutson, John M

    2008-11-01

    The cause of testicular ectopia has long been a mystery, and over the years, many hypotheses have been suggested to explain the condition. The most famous of these hypotheses is that of the 'Tails of Lockwood'. This developed from a paper written in 1888 by Charles Barrett Lockwood. Although little evidence has ever been found to corroborate this hypothesis, it remains in many textbooks and journal articles to the present day. In the 21st century, this theory should no longer be given as the cause for ectopic testes. Current biological evidence supports a complex process of growth, by elongation and migration of the gubernaculum, rather than a simple mechanical process of testicular descent, as proposed in the 18th century.

  20. Histone deacetylase inhibitors in cancer therapy.

    Science.gov (United States)

    Lane, Andrew A; Chabner, Bruce A

    2009-11-10

    Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials. HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

  1. Histones bundle F-actin filaments and affect actin structure.

    Science.gov (United States)

    Blotnick, Edna; Sol, Asaf; Muhlrad, Andras

    2017-01-01

    Histones are small polycationic proteins complexed with DNA located in the cell nucleus. Upon apoptosis they are secreted from the cells and react with extracellular polyanionic compounds. Actin which is a polyanionic protein, is also secreted from necrotic cells and interacts with histones. We showed that both histone mixture (histone type III) and the recombinant H2A histone bundles F-actin, increases the viscosity of the F-actin containing solution and polymerizes G-actin. The histone-actin bundles are relatively insensitive to increase of ionic strength, unlike other polycation, histatin, lysozyme, spermine and LL-37 induced F-actin bundles. The histone-actin bundles dissociate completely only in the presence of 300-400 mM NaCl. DNA, which competes with F-actin for histones, disassembles histone induced actin bundles. DNase1, which depolymerizes F- to G-actin, actively unbundles the H2A histone induced but slightly affects the histone mixture induced actin bundles. Cofilin decreases the amount of F-actin sedimented by low speed centrifugation, increases light scattering and viscosity of F-actin-histone mixture containing solutions and forms star like superstructures by copolymerizing G-actin with H2A histone. The results indicate that histones are tightly attached to F-actin by strong electrostatic and hydrophobic forces. Since both histones and F-actin are present in the sputum of patients with cystic fibrosis, therefore, the formation of the stable histone-actin bundles can contribute to the pathology of this disease by increasing the viscosity of the sputum. The actin-histone interaction in the nucleus might affect gene expression.

  2. Histones bundle F-actin filaments and affect actin structure.

    Directory of Open Access Journals (Sweden)

    Edna Blotnick

    Full Text Available Histones are small polycationic proteins complexed with DNA located in the cell nucleus. Upon apoptosis they are secreted from the cells and react with extracellular polyanionic compounds. Actin which is a polyanionic protein, is also secreted from necrotic cells and interacts with histones. We showed that both histone mixture (histone type III and the recombinant H2A histone bundles F-actin, increases the viscosity of the F-actin containing solution and polymerizes G-actin. The histone-actin bundles are relatively insensitive to increase of ionic strength, unlike other polycation, histatin, lysozyme, spermine and LL-37 induced F-actin bundles. The histone-actin bundles dissociate completely only in the presence of 300-400 mM NaCl. DNA, which competes with F-actin for histones, disassembles histone induced actin bundles. DNase1, which depolymerizes F- to G-actin, actively unbundles the H2A histone induced but slightly affects the histone mixture induced actin bundles. Cofilin decreases the amount of F-actin sedimented by low speed centrifugation, increases light scattering and viscosity of F-actin-histone mixture containing solutions and forms star like superstructures by copolymerizing G-actin with H2A histone. The results indicate that histones are tightly attached to F-actin by strong electrostatic and hydrophobic forces. Since both histones and F-actin are present in the sputum of patients with cystic fibrosis, therefore, the formation of the stable histone-actin bundles can contribute to the pathology of this disease by increasing the viscosity of the sputum. The actin-histone interaction in the nucleus might affect gene expression.

  3. Small molecule inhibitors of histone deacetylases and acetyltransferases as potential therapeutics in oncology

    NARCIS (Netherlands)

    van den Bosch, Thea; Leus, Niek; Timmerman, Tirza; Dekker, Frank J

    2016-01-01

    Uncontrolled cell proliferation and resistance to apoptosis in cancer are, among others, regulated by post-translational modifications of histone proteins. The most investigated type of histone modification is lysine acetylation. Histone acetyltransferases (HATs), acetylate histone lysine residues,

  4. A quantitative investigation of linker histone interactions with nucleosomes and chromatin

    Science.gov (United States)

    White, Alison E.; Hieb, Aaron R.; Luger, Karolin

    2016-01-01

    Linker histones such as H1 are abundant basic proteins that bind tightly to nucleosomes, thereby acting as key organizers of chromatin structure. The molecular details of linker histone interactions with the nucleosome, and in particular the contributions of linker DNA and of the basic C-terminal tail of H1, are controversial. Here we combine rigorous solution-state binding assays with native gel electrophoresis and Atomic Force Microscopy, to quantify the interaction of H1 with chromatin. We find that H1 binds nucleosomes and nucleosomal arrays with very tight affinity by recognizing a specific DNA geometry minimally consisting of a solitary nucleosome with a single ~18 base pair DNA linker arm. The association of H1 alters the conformation of trinucleosomes so that only one H1 can bind to the two available linker DNA regions. Neither incorporation of the histone variant H2A.Z, nor the presence of neighboring nucleosomes affects H1 affinity. Our data provide a comprehensive thermodynamic framework for this ubiquitous chromatin architectural protein. PMID:26750377

  5. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination.

    Science.gov (United States)

    Qin, Weihua; Wolf, Patricia; Liu, Nan; Link, Stephanie; Smets, Martha; La Mastra, Federica; Forné, Ignasi; Pichler, Garwin; Hörl, David; Fellinger, Karin; Spada, Fabio; Bonapace, Ian Marc; Imhof, Axel; Harz, Hartmann; Leonhardt, Heinrich

    2015-08-01

    DNMT1 is recruited by PCNA and UHRF1 to maintain DNA methylation after replication. UHRF1 recognizes hemimethylated DNA substrates via the SRA domain, but also repressive H3K9me3 histone marks with its TTD. With systematic mutagenesis and functional assays, we could show that chromatin binding further involved UHRF1 PHD binding to unmodified H3R2. These complementation assays clearly demonstrated that the ubiquitin ligase activity of the UHRF1 RING domain is required for maintenance DNA methylation. Mass spectrometry of UHRF1-deficient cells revealed H3K18 as a novel ubiquitination target of UHRF1 in mammalian cells. With bioinformatics and mutational analyses, we identified a ubiquitin interacting motif (UIM) in the N-terminal regulatory domain of DNMT1 that binds to ubiquitinated H3 tails and is essential for DNA methylation in vivo. H3 ubiquitination and subsequent DNA methylation required UHRF1 PHD binding to H3R2. These results show the manifold regulatory mechanisms controlling DNMT1 activity that require the reading and writing of epigenetic marks by UHRF1 and illustrate the multifaceted interplay between DNA and histone modifications. The identification and functional characterization of the DNMT1 UIM suggests a novel regulatory principle and we speculate that histone H2AK119 ubiquitination might also lead to UIM-dependent recruitment of DNMT1 and DNA methylation beyond classic maintenance.

  6. Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin.

    Science.gov (United States)

    Eustermann, Sebastian; Yang, Ji-Chun; Law, Martin J; Amos, Rachel; Chapman, Lynda M; Jelinska, Clare; Garrick, David; Clynes, David; Gibbons, Richard J; Rhodes, Daniela; Higgs, Douglas R; Neuhaus, David

    2011-06-12

    Accurate read-out of chromatin modifications is essential for eukaryotic life. Mutations in the gene encoding X-linked ATRX protein cause a mental-retardation syndrome, whereas wild-type ATRX protein targets pericentric and telomeric heterochromatin for deposition of the histone variant H3.3 by means of a largely unknown mechanism. Here we show that the ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. In vivo experiments show this combinatorial readout is required for ATRX localization, with recruitment enhanced by a third interaction through heterochromatin protein-1 (HP1) that also recognizes trimethylated Lys9. The cooperation of ATRX ADD domain and HP1 in chromatin recruitment results in a tripartite interaction that may span neighboring nucleosomes and illustrates how the 'histone-code' is interpreted by a combination of multivalent effector-chromatin interactions.

  7. Langmuir monolayers composed of single and double tail sulfobetaine lipids.

    Science.gov (United States)

    Hazell, Gavin; Gee, Anthony P; Arnold, Thomas; Edler, Karen J; Lewis, Simon E

    2016-07-15

    Owing to structural similarities between sulfobetaine lipids and phospholipids it should be possible to form stable Langmuir monolayers from long tail sulfobetaines. By modification of the density of lipid tail group (number of carbon chains) it should also be possible to modulate the two-dimensional phase behaviour of these lipids and thereby compare with that of equivalent phospholipids. Potentially this could enable the use of such lipids for the wide array of applications that currently use phospholipids. The benefit of using sulfobetaine lipids is that they can be synthesised by a one-step reaction from cheap and readily available starting materials and will degrade via different pathways than natural lipids. The molecular architecture of the lipid can be easily modified allowing the design of lipids for specific purposes. In addition the reversal of the charge within the sulfobetaine head group relative to the charge orientation in phospholipids may modify behaviour and thereby allow for novel uses of these surfactants. Stable Langmuir monolayers were formed composed of single and double tailed sulfobetaine lipids. Surface pressure-area isotherm, Brewster Angle Microscopy and X-ray and neutron reflectometry measurements were conducted to measure the two-dimensional phase behaviour and out-of-plane structure of the monolayers as a function of molecular area. Sulfobetaine lipids are able to form stable Langmuir monolayers with two dimensional phase behaviour analogous to that seen for the well-studied phospholipids. Changing the number of carbon tail groups on the lipid from one to two promotes the existence of a liquid condensed phase due to increased Van der Waals interactions between the tail groups. Thus the structure of the monolayers appears to be defined by the relative sizes of the head and tail groups in a predictable way. However, the presence of sub-phase ions has little effect on the monolayer structure, behaviour that is surprisingly different to

  8. Replicating chromatin: a tale of histones

    DEFF Research Database (Denmark)

    Groth, Anja

    2009-01-01

    framework of chromatin and carry information to specify higher-order organization and gene expression. When replication forks traverse the chromosomes, nucleosomes are transiently disrupted, allowing the replication machinery to gain access to DNA. Histone recycling, together with new deposition, ensures...... reassembly on nascent DNA strands. The aim of this review is to discuss how histones - new and old - are handled at the replication fork, highlighting new mechanistic insights and revisiting old paradigms.......Chromatin serves structural and functional roles crucial for genome stability and correct gene expression. This organization must be reproduced on daughter strands during replication to maintain proper overlay of epigenetic fabric onto genetic sequence. Nucleosomes constitute the structural...

  9. Mercury's Dynamic Magnetic Tail

    Science.gov (United States)

    Slavin, James A.

    2010-01-01

    The Mariner 10 and MESSENGER flybys of Mercury have revealed a magnetosphere that is likely the most responsive to upstream interplanetary conditions of any in the solar system. The source of the great dynamic variability observed during these brief passages is due to Mercury's proximity to the Sun and the inverse proportionality between reconnection rate and solar wind Alfven Mach number. However, this planet's lack of an ionosphere and its small physical dimensions also contribute to Mercury's very brief Dungey cycle, approx. 2 min, which governs the time scale for internal plasma circulation. Current observations and understanding of the structure and dynamics of Mercury's magnetotail are summarized and discussed. Special emphasis will be placed upon such questions as: 1) How much access does the solar wind have to this small magnetosphere as a function of upstream conditions? 2) What roles do heavy planetary ions play? 3) Do Earth-like substorms take place at Mercury? 4) How does Mercury's tail respond to extreme solar wind events such coronal mass ejections? Prospects for progress due to advances in the global magnetohydrodynamic and hybrid simulation modeling and the measurements to be taken by MESSENGER after it enters Mercury orbit on March 18, 2011 will be discussed.

  10. TAIL ASYMPTOTICS OF LIGHT-TAILED WEIBULL-LIKE SUMS

    DEFF Research Database (Denmark)

    Asmussen, Soren; Hashorva, Enkelejd; Laub, Patrick J.

    2017-01-01

    We consider sums of n i.i.d. random variables with tails close to exp{-x(beta)} for some beta > 1. Asymptotics developed by Rootzen (1987) and Balkema, Kluppelberg, and Resnick (1993) are discussed from the point of view of tails rather than of densities, using a somewhat different angle......, and supplemented with bounds, results on a random number N of terms, and simulation algorithms....

  11. Plant Responses to Abiotic Stress Regulated by Histone Deacetylases

    Directory of Open Access Journals (Sweden)

    Ming Luo

    2017-12-01

    Full Text Available In eukaryotic cells, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are modulated by histone acetyltransferases and histone deacetylases (HDACs. Recent studies indicate that HDACs play essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance regarding the plant HDACs and their functions in the regulation of abiotic stress responses. The role of HDACs in autophagy was also discussed.

  12. Recent advances of histone modification in gastric cancer

    Directory of Open Access Journals (Sweden)

    Wen-Yan Yang

    2014-01-01

    Full Text Available Epigenetics play important roles during development progress of tumor. The histone modifications are the most important constituted field. Recently, accumulating research focused on exploring the roles of those modifications in regulating tumorigenesis. Moreover, the dysregulation of histone modifications is supposed to have vital clinical significance. Numerous histone modifications have the potential to be prognostic biomarkers, monitoring response of therapy, early diagnostic markers. Herein, we review the recent advances of histone modifications involving development of gastric cancer.

  13. H3K23me1 is an evolutionarily conserved histone modification associated with CG DNA methylation in Arabidopsis.

    Science.gov (United States)

    Trejo-Arellano, Minerva S; Mahrez, Walid; Nakamura, Miyuki; Moreno-Romero, Jordi; Nanni, Paolo; Köhler, Claudia; Hennig, Lars

    2017-04-01

    Amino-terminal tails of histones are targets for diverse post-translational modifications whose combinatorial action may constitute a code that will be read and interpreted by cellular proteins to define particular transcriptional states. Here, we describe monomethylation of histone H3 lysine 23 (H3K23me1) as a histone modification not previously described in plants. H3K23me1 is an evolutionarily conserved mark in diverse species of flowering plants. Chromatin immunoprecipitation followed by high-throughput sequencing in Arabidopsis thaliana showed that H3K23me1 was highly enriched in pericentromeric regions and depleted from chromosome arms. In transposable elements it co-localized with CG, CHG and CHH DNA methylation as well as with the heterochromatic histone mark H3K9me2. Transposable elements are often rich in H3K23me1 but different families vary in their enrichment: LTR-Gypsy elements are most enriched and RC/Helitron elements are least enriched. The histone methyltransferase KRYPTONITE and normal DNA methylation were required for normal levels of H3K23me1 on transposable elements. Immunostaining experiments confirmed the pericentromeric localization and also showed mild enrichment in less condensed regions. Accordingly, gene bodies of protein-coding genes had intermediate H3K23me1 levels, which coexisted with CG DNA methylation. Enrichment of H3K23me1 along gene bodies did not correlate with transcription levels. Together, this work establishes H3K23me1 as a so far undescribed component of the plant histone code. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  14. Anisotropic Electron Tail Generation during Tearing Mode Magnetic Reconnection

    Science.gov (United States)

    Dubois, Ami

    2017-10-01

    Magnetic reconnection (MR) plays an important role in particle transport, energization, and acceleration in space, astrophysical, and laboratory plasmas. In the MST RFP, discrete MR events release large amounts of energy from the equilibrium magnetic field, a large fraction of which is transferred to the ions in a non-collisional process. Key features are anisotropic heating, mass and charge dependence, and energetic ion tail formation. Unlike the ions, the thermal electron temperature decreases at MR events, which is consistent with enhanced electron heat transport due to increased magnetic stochasticity. However, new high-speed x-ray spectrum measurements reveal transient formation of a non-Maxwellian energetic electron tail during MR. The energetic tail is characterized by a power-law, E-γ, with the spectral index (γ) decreasing from 4.2 to 2.2 at MR, and then increasing rapidly to 6.8 due to increased stochastic transport. The x-ray emission peaks in a radial view and is symmetric in the toroidal direction, indicating an anisotropic electron tail is generated. The toroidal symmetry of the electron tail implies runaway acceleration is not a dominant process, consistent with the net emf, ηJll, being smaller than the Dreicer field. Modeling of bremsstrahlung emission shows that a power-law electron tail distribution that is localized near the magnetic axis will yield strong perpendicular anisotropy, consistent with x-ray measurements in the radial and toroidal views. A strong correlation between high energy x-ray flux and tearing mode dynamics suggests a turbulent mechanism is active. This implies that the electron tail formation most likely results from a turbulent wave-particle interaction. This work is supported by the US DOE and NSF.

  15. Histone methylations in heart development, congenital and adult heart diseases

    OpenAIRE

    Zhang, Qing-Jun; Liu, Zhi-Ping

    2015-01-01

    Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers duri...

  16. Trichostatin A induced histone acetylation causes decondensation of interphase chromatin.

    NARCIS (Netherlands)

    T.A. Knoch (Tobias); M. Wachsmuth (Malte); M. Frank-Stöhr (Monika); M. Stöhr (Michael); C.P. Bacher (Christian); K. Rippe (Karsten)

    2004-01-01

    textabstractThe effect of trichostatin A (TSA)-induced histone acetylation on the interphase chromatin structure was visualized in vivo with a HeLa cell line stably expressing histone H2A, which was fused to enhanced yellow fluorescent protein. The globally increased histone acetylation caused a

  17. More tail lesions among undocked than tail docked pigs in a conventional herd

    DEFF Research Database (Denmark)

    Lahrmann, H. P.; Busch, M. E.; D'Eath, R. B.

    2017-01-01

    The vast majority of piglets reared in the European Union (EU) and worldwide is tail docked to reduce the risk of being tail bitten, even though EU animal welfare legislation bans routine tail docking. Many conventional herds experience low levels of tail biting among tail docked pigs, however...... it is not known, what the prevalence would have been had the pigs not been tail docked. The aim of this study was to compare the prevalence of tail lesions between docked and undocked pigs in a conventional piggery in Denmark with very low prevalence of tail biting among tail docked pigs. The study included 1922...... that housing pigs with intact tails in conventional herds with very low prevalence of tail biting among tail docked pigs, will increase the prevalence of pigs with tail lesions considerably, and pig producers will need more hospital pens. Abattoir data indicate that tail biting remarks from meat inspection...

  18. Tails, Fears and Risk Premia

    DEFF Research Database (Denmark)

    Bollerslev, Tim; Todorov, Victor

    We show that the compensation for rare events accounts for a large fraction of the equity and variance risk premia in the S&P 500 market index. The probability of rare events vary significantly over time, increasing in periods of high market volatility, but the risk premium for tail events cannot...... solely be explained by the level of the volatil- ity. Our empirical investigations are essentially model-free. We estimate the expected values of the tails under the statistical probability measure from "medium" size jumps in high-frequency intraday prices and an extreme value theory approximation...... for the corresponding jump tail density. Our estimates for the risk-neutral expectations are based on short maturity out-of-the money options and new model-free option implied variation measures explicitly designed to separate the tail probabilities. At a general level, our results suggest that any satisfactory...

  19. Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

    Directory of Open Access Journals (Sweden)

    Cabrera Gustavo

    2005-07-01

    Full Text Available Abstract Background The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. Methods Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each: 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. Results All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%, whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p Conclusion Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.

  20. Expanding the Reader Landscape of Histone Acylation.

    Science.gov (United States)

    Khan, Abid; Bridgers, Joseph B; Strahl, Brian D

    2017-04-04

    In this issue of Structure,Klein et al. (2017) expand our understanding of what reader domains bind to by showing that MORF, a double PHD domain containing lysine acetyltransferase, is a preferential reader of histone lysine acylation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Histone deacetylases in memory and cognition.

    Science.gov (United States)

    Penney, Jay; Tsai, Li-Huei

    2014-12-09

    Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease. Copyright © 2014, American Association for the Advancement of Science.

  2. Another twist in the histone memory code.

    Science.gov (United States)

    Josselyn, Sheena; Frankland, Paul W

    2015-02-01

    Transcription is a highly regulated process and several studies have examined the role of transcription factors and various epigenetic regulators in memory formation. In a recent paper in Nature, Zokvic and colleagues show an important role for a novel regulator of chromatin structure (the incorporation of histone variants) in memory formation.

  3. CHARGE IMBALANCE

    Energy Technology Data Exchange (ETDEWEB)

    Clarke, John

    1980-09-01

    The purpose of this article is to review the theory of charge imbalance, and to discuss its relevance to a number of experimental situations. We introduce the concepts of quasiparticle charge and charge imbalance, and discuss the generation and detection of charge imbalance by tunneling. We describe the relaxation of the injected charge imbalance by inelastic scattering processes, and show how the Boltzmann equation can be solved to obtain the steady state quasiparticle distribution and the charge relaxation rate. Details are given of experiments to measure charge imbalance and the charge relaxation rate when inelastic scattering is the predominant relaxation mechanism. Experiments on and theories of other charge relaxation mechanisms are discussed, namely relaxation via elastic scattering in the presence of energy gap anisotropy, or in the presence of a pair breaking mechanism such as magnetic impurities or an applied supercurrent or magnetic field. We describe three other situations in which charge imbalance occurs, namely the resistance of the NS interface, phase slip centers, and the flow of a supercurrent in the presence of a temperature gradient.

  4. Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications.

    Science.gov (United States)

    Monteiro, Janice B; Colón-Díaz, Maricarmen; García, Miosotis; Gutierrez, Sylvia; Colón, Mariano; Seto, Edward; Laboy, Joaquín; Flores, Idhaliz

    2014-03-01

    The histone modification patterns in endometriosis have not been fully characterized. This gap in knowledge results in a poor understanding of the epigenetic mechanisms (and potential therapeutic targets) at play. We aimed to (1) assess global acetylation status of histone 3 (H3) and histone 4 (H4), (2) measure levels of H3 and H4 lysine (K) acetylation and methylation, and (3) to identify histone acetylation patterns in promoter regions of candidate genes in tissues from patients and controls. Global and K-specific acetylation/methylation levels of histones were measured in 24 lesions, 15 endometrium from patients, and 26 endometrium from controls. Chromatin immunoprecipitation (ChIP)-polymerase chain reaction was used to determine the histone acetylation status of the promoter regions of candidate genes in tissues. The lesions were globally hypoacetylated at H3 (but not H4) compared to eutopic endometrium from controls. Lesions had significantly lower levels of H3K9ac and H4K16ac compared to eutopic endometrium from patients and controls. Tissues from patients were hypermethylated at H3K4, H3K9, and H3K27 compared to endometrium from controls. The ChIP analysis showed hypoacetylation of H3/H4 within promoter regions of candidate genes known to be downregulated in endometriosis (e.g., HOXA10, ESR1, CDH1, and p21 (WAF1/Cip1) ) in lesions versus control endometrium. The stereoidogenic factor 1 (SF1) promoter region was enriched for acetylated H3 and H4 in lesions versus control tissues, correlating with its reported high expression in lesions. This study describes the histone code of lesions and endometrium from patients with endometriosis and provides support for a possible role of histone modification in modulation of gene expression in endometriosis.

  5. A Novel Histone Crosstalk Pathway Important for Regulation of UV-Induced DNA Damage Repair in Saccharomyces cerevisiae.

    Science.gov (United States)

    Boudoures, Anna L; Pfeil, Jacob J; Steenkiste, Elizabeth M; Hoffman, Rachel A; Bailey, Elizabeth A; Wilkes, Sara E; Higdon, Sarah K; Thompson, Jeffrey S

    2017-07-01

    Histone post-translational modifications play vital roles in a variety of nuclear processes, including DNA repair. It has been previously shown that histone H3K79 methylation is important for the cellular response to DNA damage caused by ultraviolet (UV) radiation, with evidence that specific methylation states play distinct roles in UV repair. Here, we report that H3K79 methylation is reduced in response to UV exposure in Saccharomyces cerevisiae This reduction is specific to the dimethylated state, as trimethylation levels are minimally altered by UV exposure. Inhibition of this reduction has a deleterious effect on UV-induced sister chromatid exchange, suggesting that H3K79 dimethylation levels play a regulatory role in UV repair. Further evidence implicates an additional role for H3K79 dimethylation levels in error-free translesion synthesis, but not in UV-induced G1/S checkpoint activation or double-stranded break repair. Additionally, we find that H3K79 dimethylation levels are influenced by acetylatable lysines on the histone H4 N-terminal tail, which are hyperacetylated in response to UV exposure. Preclusion of H4 acetylation prevents UV-induced reduction of H3K79 dimethylation, and similarly has a negative effect on UV-induced sister chromatid exchange. These results point to the existence of a novel histone crosstalk pathway that is important for the regulation of UV-induced DNA damage repair. Copyright © 2017 by the Genetics Society of America.

  6. Varieties of charge distributions in coat proteins of ssRNA+  viruses

    Science.gov (United States)

    Lošdorfer Božič, Anže; Podgornik, Rudolf

    2018-01-01

    A major part of the interactions involved in the assembly and stability of icosahedral, positive-sense single-stranded RNA (ssRNA+) viruses is electrostatic in nature, as can be inferred from the strong pH- and salt-dependence of their assembly phase diagrams. Electrostatic interactions do not act only between the capsid coat proteins (CPs), but just as often provide a significant contribution to the interactions of the CPs with the genomic RNA, mediated to a large extent by positively charged, flexible N-terminal tails of the CPs. In this work, we provide two clear and complementary definitions of an N-terminal tail of a protein, and use them to extract the tail sequences of a large number of CPs of ssRNA+  viruses. We examine the pH-dependent interplay of charge on both tails and CPs alike, and show that—in contrast to the charge on the CPs—the net positive charge on the N-tails persists even to very basic pH values. In addition, we note a limit to the length of the wild-type genomes of those viruses which utilize positively charged tails, when compared to viruses without charged tails and similar capsid size. At the same time, we observe no clear connection between the charge on the N-tails and the genome lengths of the viruses included in our study.

  7. dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing

    NARCIS (Netherlands)

    A. Lagarou (Anna); A.B. Mohd Sarip; Y.M. Moshkin (Yuri); G.E. Chalkley (Gillian); K. Bezstarosti (Karel); J.A.A. Demmers (Jeroen); C.P. Verrijzer (Peter)

    2008-01-01

    textabstractTranscription regulation involves enzyme-mediated changes in chromatin structure. Here, we describe a novel mode of histone crosstalk during gene silencing, in which histone H2A monoubiquitylation is coupled to the removal of histone H3 Lys 36 dimethylation (H3K36me2). This pathway was

  8. Disturbing the histone code in leukemia: translocations and mutations affecting histone methyl transferases.

    Science.gov (United States)

    Chopra, Martin; Bohlander, Stefan K

    2015-05-01

    Leukemia is characterized by increased numbers of blasts originating from transformed early hematopoietic stem and progenitor cells. Genetic alterations are widely recognized as the main drivers of oncogenic transformation. Of considerable interest are mutations affecting the writers of epigenetic marks. In this review, we focus on histone methyltransferases--enzymes that catalyze the methylation of lysine residues in core histones. Histone methylation is a tightly controlled mechanism that is responsible for both activating as well as repressing gene expression in a site-specific manner, depending on which lysine residue is methylated. Histone methyltransferases, including MLL1, DOT1L, EZH2, and SETD2 are recurrently deregulated in human leukemia, either directly by gene mutations or balanced translocations, or indirectly as components of protein complexes that are disturbed in leukemia due to alterations of the other components in these complexes. Several small molecule inhibitors of histone methyltransferases are currently being clinically evaluated for their therapeutic potential in human leukemia. These drugs reverse some of the adverse effects of aberrant histone methylation, and can induce differentiation and cell death in leukemic blasts. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation

    Energy Technology Data Exchange (ETDEWEB)

    Bian, Chuanbing; Xu, Chao; Ruan, Jianbin; Lee, Kenneth K.; Burke, Tara L.; Tempel, Wolfram; Barsyte, Dalia; Li, Jing; Wu, Minhao; Zhou, Bo O.; Fleharty, Brian E.; Paulson, Ariel; Allali-Hassani, Abdellah; Zhou, Jin-Qiu; Mer, Georges; Grant, Patrick A.; Workman, Jerry L.; Zang, Jianye; Min, Jinrong (Toronto); (Stowers); (UST - China); (UV); (Chinese Aca. Sci.); (MCCM)

    2011-09-28

    The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an important chromatin modifying complex that can both acetylate and deubiquitinate histones. Sgf29 is a novel component of the SAGA complex. Here, we report the crystal structures of the tandem Tudor domains of Saccharomyces cerevisiae and human Sgf29 and their complexes with H3K4me2 and H3K4me3 peptides, respectively, and show that Sgf29 selectively binds H3K4me2/3 marks. Our crystal structures reveal that Sgf29 harbours unique tandem Tudor domains in its C-terminus. The tandem Tudor domains in Sgf29 tightly pack against each other face-to-face with each Tudor domain harbouring a negatively charged pocket accommodating the first residue alanine and methylated K4 residue of histone H3, respectively. The H3A1 and K4me3 binding pockets and the limited binding cleft length between these two binding pockets are the structural determinants in conferring the ability of Sgf29 to selectively recognize H3K4me2/3. Our in vitro and in vivo functional assays show that Sgf29 recognizes methylated H3K4 to recruit the SAGA complex to its targets sites and mediates histone H3 acetylation, underscoring the importance of Sgf29 in gene regulation.

  10. Histones have high affinity for the glomerular basement membrane. Relevance for immune complex formation in lupus nephritis

    Energy Technology Data Exchange (ETDEWEB)

    Schmiedeke, T.M.; Stoeckl, F.W.W.; Weber, R.; Sugisaki, Y.; Batsford, S.R.; Vogt, A.

    1989-06-01

    An effort has been made to integrate insights on charge-based interactions in immune complex glomerulonephritis with nuclear antigen involvement in lupus nephritis. Attention was focussed on the histones, a group of highly cationic nuclear constituents, which could be expected to bind to fixed anionic sites present in the glomerular basement membrane (GBM). We demonstrated that all histone subfractions, prepared according to Johns, have a high affinity for GBM and the basement membrane of peritubular capillaries. Tissue uptake of /sup 125/I-labeled histones was measured by injecting 200 micrograms of each fraction into the left kidney via the aorta and measuring organ uptake after 15 min. In glomeruli isolated from the left kidneys, the following quantities of histones were found: f1, 13 micrograms; f2a (f2al + f2a2), 17 micrograms; f2b, 17 micrograms; and f3, 32 micrograms. Kinetic studies of glomerular binding showed that f1 disappeared much more rapidly than f2a. The high affinity of histones (pI between 10.5 and 11.0; mol wt 10,000-22,000) for the GBM correlates well with their ability to form aggregates (mol wt greater than 100,000) for comparison lysozyme (pI 11, mol wt 14,000), which does not aggregate spontaneously bound poorly (0.4 micrograms in isolated glomeruli). The quantity of histones and lysozyme found in the isolated glomeruli paralleled their in vitro affinity for a Heparin-Sepharose column (gradient elution studies). This gel matrix contains the sulfated, highly anionic polysaccharide heparin, which is similar to the negatively charged heparan sulfate present in the GBM. Lysozyme eluted with 0.15 M NaCl, f1 with 1 M NaCl, and f2a, f2b, and f3 could not be fully desorbed even with 2 M NaCl; 6 M guanidine-HCl was necessary.

  11. SUBAQUEOUS DISPOSAL OF MILL TAILINGS

    Energy Technology Data Exchange (ETDEWEB)

    Neeraj K. Mendiratta; Roe-Hoan Yoon; Paul Richardson

    1999-09-03

    A study of mill tailings and sulfide minerals was carried out in order to understand their behavior under subaqueous conditions. A series of electrochemical experiments, namely, cyclic voltammetry, electrochemical impedance spectroscopy and galvanic coupling tests were carried out in artificial seawater and in pH 6.8 buffer solutions with chloride and ferric salts. Two mill tailings samples, one from the Kensington Mine, Alaska, and the other from the Holden Mine, Washington, were studied along with pyrite, galena, chalcopyrite and copper-activated sphalerite. SEM analysis of mill tailings revealed absence of sulfide minerals from the Kensington Mine mill tailings, whereas the Holden Mine mill tailings contained approximately 8% pyrite and 1% sphalerite. In order to conduct electrochemical tests, carbon matrix composite (CMC) electrodes of mill tailings, pyrite and galena were prepared and their feasibility was established by conducting a series of cyclic voltammetry tests. The cyclic voltammetry experiments carried out in artificial seawater and pH 6.8 buffer with chloride salts showed that chloride ions play an important role in the redox processes of sulfide minerals. For pyrite and galena, peaks were observed for the formation of chloride complexes, whereas pitting behavior was observed for the CMC electrodes of the Kensington Mine mill tailings. The electrochemical impedance spectroscopy conducted in artificial seawater provided with the Nyquist plots of pyrite and galena. The Nyquist plots of pyrite and galena exhibited an inert range of potential indicating a slower rate of leaching of sulfide minerals in marine environments. The galvanic coupling experiments were carried out to study the oxidation of sulfide minerals in the absence of oxygen. It was shown that in the absence of oxygen, ferric (Fe3+) ions might oxidize the sulfide minerals, thereby releasing undesirable oxidation products in the marine environment. The source of Fe{sup 3{minus}} ions may be

  12. Internal Charging

    Science.gov (United States)

    Minow, Joseph I.

    2014-01-01

    (1) High energy (>100keV) electrons penetrate spacecraft walls and accumulate in dielectrics or isolated conductors; (2) Threat environment is energetic electrons with sufficient flux to charge circuit boards, cable insulation, and ungrounded metal faster than charge can dissipate; (3) Accumulating charge density generates electric fields in excess of material breakdown strenght resulting in electrostatic discharge; and (4) System impact is material damage, discharge currents inside of spacecraft Faraday cage on or near critical circuitry, and RF noise.

  13. Citrullination regulates pluripotency and histone H1 binding to chromatin

    Science.gov (United States)

    Christophorou, Maria A.; Castelo-Branco, Gonçalo; Halley-Stott, Richard P.; Oliveira, Clara Slade; Loos, Remco; Radzisheuskaya, Aliaksandra; Mowen, Kerri A.; Bertone, Paul; Silva, José C. R.; Zernicka-Goetz, Magdalena; Nielsen, Michael L.; Gurdon, John B.; Kouzarides, Tony

    2014-03-01

    Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline. This modification leads to the loss of a positive charge and reduction in hydrogen-bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis. Nevertheless, the physiological functions of citrullination remain ill-defined, although citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection. Here we show that the expression and enzymatic activity of Padi4 are also induced under conditions of ground-state pluripotency and during reprogramming in mouse. Padi4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem-cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin, as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA-binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.

  14. Systems Level Analysis of Histone H3 Post-translational Modifications (PTMs) Reveals Features of PTM Crosstalk in Chromatin Regulation

    DEFF Research Database (Denmark)

    Schwämmle, Veit; Sidoli, Simone; Ruminowicz, Chrystian

    2016-01-01

    molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse....... We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks......, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37...

  15. Histone phosphorylation: a chromatin modification involved in diverse nuclear events.

    Science.gov (United States)

    Rossetto, Dorine; Avvakumov, Nikita; Côté, Jacques

    2012-10-01

    Histone posttranslational modifications are key components of diverse processes that modulate chromatin structure. These marks function as signals during various chromatin-based events, and act as platforms for recruitment, assembly or retention of chromatin-associated factors. The best-known function of histone phosphorylation takes place during cellular response to DNA damage, when phosphorylated histone H2A(X) demarcates large chromatin domains around the site of DNA breakage. However, multiple studies have also shown that histone phosphorylation plays crucial roles in chromatin remodeling linked to other nuclear processes. In this review, we summarize the current knowledge of histone phosphorylation and describe the many kinases and phosphatases that regulate it. We discuss the key roles played by this histone mark in DNA repair, transcription and chromatin compaction during cell division and apoptosis. Additionally, we describe the intricate crosstalk that occurs between phosphorylation and other histone modifications and allows for sophisticated control over the chromatin remodeling processes.

  16. Regulation of replication fork progression through histone supply and demand

    DEFF Research Database (Denmark)

    Groth, Anja; Corpet, Armelle; Cook, Adam J L

    2007-01-01

    DNA replication in eukaryotes requires nucleosome disruption ahead of the replication fork and reassembly behind. An unresolved issue concerns how histone dynamics are coordinated with fork progression to maintain chromosomal stability. Here, we characterize a complex in which the human histone......1 chaperone function, histone supply, and replicative unwinding of DNA in chromatin. We propose that Asf1, as a histone acceptor and donor, handles parental and new histones at the replication fork via an Asf1-(H3-H4)-MCM2-7 intermediate and thus provides a means to fine-tune replication fork...... chaperone Asf1 and MCM2-7, the putative replicative helicase, are connected through a histone H3-H4 bridge. Depletion of Asf1 by RNA interference impedes DNA unwinding at replication sites, and similar defects arise from overproduction of new histone H3-H4 that compromises Asf1 function. These data link Asf...

  17. Research on Long Tail Recommendation Algorithm

    Science.gov (United States)

    Hu, Xuezhi; Zhang, Chuang; Wu, Ming; Zeng, Yang

    2017-10-01

    Most recommendation systems in the major electronic commerce platforms are influenced by the long tail effect more or less. There are sufficient researches of how to assess recommendation effect while no criteria to evaluate long tail recommendation rate. In this study, we first discussed the existing problems of recommending long tail products through specific experiments. Then we proposed a long tail evaluation criteria and compared the performance in long tail recommendation between different models.

  18. Inhibition of histone-mediated gene transfer in eucaryotic cells by anti-histone IgG.

    Science.gov (United States)

    Hasselmayer, O; Demirhan, I; Chandra, A; Bayer, M; Müller, R; Chandra, P

    2001-01-01

    In our laboratory, the gene transfer efficiency of some lipofection reagents (lipofectine, lipofectamine, DOTAP and Dosper) and histones H3 and H4 was compared to that of DEAE-Dextran (64). The histones H3 and H4 were found to have the highest transfection efficiency of all the agents tested. In the present study we have analyzed other parameters important for gene delivery by the histones H3 and H4. We transferred the HIV-1 tat gene to Jurkat cells and measured the transactivation of HIV-1-LTR by the transactivator protein, expressed in Jurkat cells. The expression of CAT as a reporter gene hybridized to LTR was a direct measure of transactivation potential. In order to investigate whether the transfection was only due to the positive ionic character of the histones H3 and H4 we tested other histones (H1 and H2A) and polylysine in our system. Under our experimental conditions, neither polylysine, nor the histones H1 and H2A were able to promote gene transfer in Jurkat cells. The inability of these reagents to promote gene transfer was not dependent on DNA condensation; in EMSA (Electrophoretic Mobility Shift Assay) all these reagents exhibited a strong retardation of DNA. In the presence of anti-histone-IgG the transfection potential of histones H3 and H4 was diminished in a concentration - dependent manner. To investigate whether the histone antibodies inhibited the condensation of DNA by histones we carried out gel retardation assays (EMSA) in the absence and in the presence of histone antibodies. Anti-histone-IgG had no effect on the retardation of histone-DNA complexes; on the contrary, retardation was increased. This observation has led us to postulate two models for the possible mechanism by which the histones H3 and H4 catalyze gene transfer in eucaryotic cells.

  19. Structure and function of histone acetyltransferase MOF.

    Science.gov (United States)

    Chen, Qiao Yi; Costa, Max; Sun, Hong

    2015-01-01

    MOF was first identified in Drosophila melanogaster as an important component of the dosage compensation complex. As a member of MYST family of histone acetyltransferase, MOF specifically deposits the acetyl groups to histone H4 lysine 16. Throughout evolution, MOF and its mammalian ortholog have retained highly conserved substrate specificity and similar enzymatic activities. MOF plays important roles in dosage compensation, ESC self-renewal, DNA damage and repair, cell survival, and gene expression regulation. Dysregulation of MOF has been implicated in tumor formation and progression of many types of human cancers. This review will discuss the structure and activity of mammalian hMOF as well as its function in H4K16 acetylation, DNA damage response, stem cell pluripotency, and carcinogenesis.

  20. Ascending the nucleosome face: recognition and function of structured domains in the histone H2A-H2B dimer.

    Science.gov (United States)

    Wyrick, John J; Kyriss, McKenna N M; Davis, William B

    2012-08-01

    Research over the past decade has greatly expanded our understanding of the nucleosome's role as a dynamic hub that is specifically recognized by many regulatory proteins involved in transcription, silencing, replication, repair, and chromosome segregation. While many of these nucleosome interactions are mediated by post-translational modifications in the disordered histone tails, it is becoming increasingly apparent that structured regions of the nucleosome, including the histone fold domains, are also recognized by numerous regulatory proteins. This review will focus on the recognition of structured domains in the histone H2A-H2B dimer, including the acidic patch, the H2A docking domain, the H2B α3-αC helices, and the HAR/HBR domains, and will survey the known biological functions of histone residues within these domains. Novel post-translational modifications and trans-histone regulatory pathways involving structured regions of the H2A-H2B dimer will be highlighted, along with the role of intrinsic disorder in the recognition of structured nucleosome regions. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. On the origin of the histone fold

    Directory of Open Access Journals (Sweden)

    Söding Johannes

    2007-03-01

    Full Text Available Abstract Background Histones organize the genomic DNA of eukaryotes into chromatin. The four core histone subunits consist of two consecutive helix-strand-helix motifs and are interleaved into heterodimers with a unique fold. We have searched for the evolutionary origin of this fold using sequence and structure comparisons, based on the hypothesis that folded proteins evolved by combination of an ancestral set of peptides, the antecedent domain segments. Results Our results suggest that an antecedent domain segment, corresponding to one helix-strand-helix motif, gave rise divergently to the N-terminal substrate recognition domain of Clp/Hsp100 proteins and to the helical part of the extended ATPase domain found in AAA+ proteins. The histone fold arose subsequently from the latter through a 3D domain-swapping event. To our knowledge, this is the first example of a genetically fixed 3D domain swap that led to the emergence of a protein family with novel properties, establishing domain swapping as a mechanism for protein evolution. Conclusion The helix-strand-helix motif common to these three folds provides support for our theory of an 'ancient peptide world' by demonstrating how an ancestral fragment can give rise to 3 different folds.

  2. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  3. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  4. Identification and characterization of the genes encoding the core histones and histone variants of Neurospora crassa.

    OpenAIRE

    Hays, Shan M; Swanson, Johanna; Eric U Selker

    2002-01-01

    We have identified and characterized the complete complement of genes encoding the core histones of Neurospora crassa. In addition to the previously identified pair of genes that encode histones H3 and H4 (hH3 and hH4-1), we identified a second histone H4 gene (hH4-2), a divergently transcribed pair of genes that encode H2A and H2B (hH2A and hH2B), a homolog of the F/Z family of H2A variants (hH2Az), a homolog of the H3 variant CSE4 from Saccharomyces cerevisiae (hH3v), and a highly diverged ...

  5. Ruin problems and tail asymptotics

    DEFF Research Database (Denmark)

    Rønn-Nielsen, Anders

    The thesis Ruin Problems and Tail Asymptotics provides results on ruin problems for several classes of Markov processes. For a class of diffusion processes with jumps an explicit expression for the joint Laplace transform of the first passage time and the corresponding undershoot is derived...

  6. Capital regulation and tail risk

    NARCIS (Netherlands)

    Perotti, E.; Ratnovski, L.; Vlahu, R.

    2011-01-01

    The paper studies risk mitigation associated with capital regulation, in a context where banks may choose tail risk assets. We show that this undermines the traditional result that higher capital reduces excess risk taking driven by limited liability. Moreover, higher capital may have an unintended

  7. Capital regulation and tail risk

    NARCIS (Netherlands)

    Perotti, E.; Ratnovski, L.; Vlahu, R.

    2011-01-01

    The paper studies risk mitigation associated with capital regulation, in a context when banks may choose tail risk assets. We show that this undermines the traditional result that higher capital reduces excess risk-taking driven by limited liability. When capital raising is costly, poorly

  8. Detection of Mercury's Potassium Tail

    Science.gov (United States)

    Schmidt, Carl; Leblanc, Francois; Moore, Luke; Bida, Thomas A.

    2017-10-01

    Ground-based observations of Mercury's exosphere bridge the gap between the MESSENGER and BepiColombo missions and provide a broad counterpart to their in situ measurements. Here we report the first detection of Mercury's potassium tail in both emission lines of the D doublet. The sodium to potassium abundance ratio at 5 planetary radii down-tail is approximately 95, near the mid-point of a wide range of values that have been quoted over the planet's disk. This is several times the Na/K present in atmospheres of the Galilean satellites and more than an order of magnitude above Mercury's usual analogue, the Moon. The observations confirm that Mercury's anomalously high Na/K ratios cannot be explained by differences in neutral loss rates. The width and structure of the Na and K tails is comparable and both exhibit a persistent enhancement in their northern lobe. We interpret this as a signature of Mercury's offset magnetosphere; the exosphere's source rates are locally enhanced at the southern surface, and sloshing from radiation pressure and gravity guides this population into the northern region of the tail.

  9. HAMLET interacts with histones and chromatin in tumor cell nuclei.

    Science.gov (United States)

    Düringer, Caroline; Hamiche, Ali; Gustafsson, Lotta; Kimura, Hiroshi; Svanborg, Catharina

    2003-10-24

    HAMLET is a folding variant of human alpha-lactalbumin in an active complex with oleic acid. HAMLET selectively enters tumor cells, accumulates in their nuclei and induces apoptosis-like cell death. This study examined the interactions of HAMLET with nuclear constituents and identified histones as targets. HAMLET was found to bind histone H3 strongly and to lesser extent histones H4 and H2B. The specificity of these interactions was confirmed using BIAcore technology and chromatin assembly assays. In vivo in tumor cells, HAMLET co-localized with histones and perturbed the chromatin structure; HAMLET was found associated with chromatin in an insoluble nuclear fraction resistant to salt extraction. In vitro, HAMLET bound strongly to histones and impaired their deposition on DNA. We conclude that HAMLET interacts with histones and chromatin in tumor cell nuclei and propose that this interaction locks the cells into the death pathway by irreversibly disrupting chromatin organization.

  10. Production and Purification of Antibodies Against Histone Modifications.

    Science.gov (United States)

    Guillemette, Benoit; Hammond-Martel, Ian; Wurtele, Hugo; Verreault, Alain

    2017-01-01

    Antibodies that recognize specific histone modifications are invaluable tools to study chromatin structure and function. There are numerous commercially available antibodies that recognize a remarkable diversity of histone modifications. Unfortunately, many of them fail to work in certain applications or lack the high degree of specificity required of these reagents. The production of affinity-purified polyclonal antibodies against histone modifications demands a little effort but, in return, provides extremely valuable tools that overcome many of the concerns and limitations of commercial antibodies. We present a series of protocols and guidelines for the production and use of large amounts of polyclonal antibodies that recognize modifications of canonical histones. Our protocols can be applied to obtain antibodies that occur in histone variants and proteins other than histones. In addition, some of our protocols are compatible with the production of monoclonal or recombinant antibodies.

  11. Determination of histone acetylation status by chromatin immunoprecipitation.

    Science.gov (United States)

    Galdieri, Luciano; Moon, John; Vancura, Ales

    2012-01-01

    Histone acetylation is the most studied posttranslation modification of nucleosomes. Understanding the mechanisms involved in global and promoter-specific histone acetylation will shed light on the control of transcriptional regulation. Chromatin immunoprecipitation is a powerful technique to study protein-DNA interactions in vivo. Proteins and DNA are cross-linked with formaldehyde, cells are lysed, and DNA is sheared by sonication. Protein-DNA complexes are immunoprecipitated with antibodies specific for total and acetylated histones and the relative occupancy of acetylated and total histones at selected loci is assessed by real-time PCR of the purified DNA.

  12. Structural and Functional Coordination of DNA and Histone Methylation

    Science.gov (United States)

    Cheng, Xiaodong

    2014-01-01

    One of the most fundamental questions in the control of gene expression in mammals is how epigenetic methylation patterns of DNA and histones are established, erased, and recognized. This central process in controlling gene expression includes coordinated covalent modifications of DNA and its associated histones. This article focuses on structural aspects of enzymatic activities of histone (arginine and lysine) methylation and demethylation and functional links between the methylation status of the DNA and histones. An interconnected network of methyltransferases, demethylases, and accessory proteins is responsible for changing or maintaining the modification status of specific regions of chromatin. PMID:25085914

  13. Cracking the death code: apoptosis-related histone modifications.

    Science.gov (United States)

    Füllgrabe, J; Hajji, N; Joseph, B

    2010-08-01

    The degradation and compaction of chromatin are long-standing hallmark features of apoptosis. The histones, chief protein components of chromatin, are subjected to a wide range of post-translational modifications. An increasing body of evidence suggests that combinations of epigenetic histone modifications influence the overall chromatin structure and have clear functional consequences in cellular processes including apoptosis. This review describes the work to date on the post-translational modification of histones during apoptosis, their regulation by enzymatic complexes and discusses the existence of the apoptotic histone code.

  14. Role of Histone Acetylation in Cell Cycle Regulation.

    Science.gov (United States)

    Koprinarova, Miglena; Schnekenburger, Michael; Diederich, Marc

    2016-01-01

    Core histone acetylation is a key prerequisite for chromatin decondensation and plays a pivotal role in regulation of chromatin structure, function and dynamics. The addition of acetyl groups disturbs histone/DNA interactions in the nucleosome and alters histone/histone interactions in the same or adjacent nucleosomes. Acetyl groups can also provide binding sites for recruitment of bromodomain (BRD)-containing non-histone readers and regulatory complexes to chromatin allowing them to perform distinct downstream functions. The presence of a particular acetylation pattern influences appearance of other histone modifications in the immediate vicinity forming the "histone code". Although the roles of the acetylation of particular lysine residues for the ongoing chromatin functions is largely studied, the epigenetic inheritance of histone acetylation is a debated issue. The dynamics of local or global histone acetylation is associated with fundamental cellular processes such as gene transcription, DNA replication, DNA repair or chromatin condensation. Therefore, it is an essential part of the epigenetic cell response to processes related to internal and external signals.

  15. MD on Head-Tail Instability in the PS Booster

    CERN Document Server

    Kornilov, V; Mikulec, B; Aumon, S; Rumolo, G

    2013-01-01

    Machine study experiments on the coherent instabilities appearing along the magnetic ramp have been performed at the CERN PS Booster synchrotron in the week of June 11-15, 2012. The space- and time structure of the head-tail instabilities was recorded by the triggered pick-up signals due to reproducibility of the occurrence time in the shot-by-shot sense. The intensity thresholds, the absolute growth rates and the mode structure have been compared for the bunches in the single-rf and in three types of the double-rf operation. The growth rates are compared to the instantaneous synchrotron frequencies, in the cases of the large corresponding ratio the head-tail mode structure is deformed by the driving impedance. Bunch parameters measurements indicate that the PSB bunches are in the regime of very strong transverse space-charge all along the magnetic ramp.

  16. Descending from infinity: convergence of tailed distributions.

    Science.gov (United States)

    Van den Broeck, Christian; Harbola, Upendra; Toral, Raul; Lindenberg, Katja

    2015-01-01

    We investigate the relaxation of long-tailed distributions under stochastic dynamics that do not support such tails. Linear relaxation is found to be a borderline case in which long tails are exponentially suppressed in time but not eliminated. Relaxation stronger than linear suppresses long tails immediately, but may lead to strong transient peaks in the probability distribution. We also find that a δ-function initial distribution under stronger than linear decay displays not one but two different regimes of diffusive spreading.

  17. Parameter Uncertainty in Exponential Family Tail Estimation

    OpenAIRE

    Landsman, Z.; Tsanakas, A.

    2012-01-01

    Actuaries are often faced with the task of estimating tails of loss distributions from just a few observations. Thus estimates of tail probabilities (reinsurance prices) and percentiles (solvency capital requirements) are typically subject to substantial parameter uncertainty. We study the bias and MSE of estimators of tail probabilities and percentiles, with focus on 1-parameter exponential families. Using asymptotic arguments it is shown that tail estimates are subject to significant positi...

  18. Rapid divergence of histones in Hydrozoa (Cnidaria) and evolution of a novel histone involved in DNA damage response in hydra.

    Science.gov (United States)

    Reddy, Puli Chandramouli; Ubhe, Suyog; Sirwani, Neha; Lohokare, Rasika; Galande, Sanjeev

    2017-08-01

    Histones are fundamental components of chromatin in all eukaryotes. Hydra, an emerging model system belonging to the basal metazoan phylum Cnidaria, provides an ideal platform to understand the evolution of core histone components at the base of eumetazoan phyla. Hydra exhibits peculiar properties such as tremendous regenerative capacity, lack of organismal senescence and rarity of malignancy. In light of the role of histone modifications and histone variants in these processes it is important to understand the nature of histones themselves and their variants in hydra. Here, we report identification of the complete repertoire of histone-coding genes in the Hydra magnipapillata genome. Hydra histones were classified based on their copy numbers, gene structure and other characteristic features. Genomic organization of canonical histone genes revealed the presence of H2A-H2B and H3-H4 paired clusters in high frequency and also a cluster with all core histones along with H1. Phylogenetic analysis of identified members of H2A and H2B histones suggested rapid expansion of these groups in Hydrozoa resulting in the appearance of unique subtypes. Amino acid sequence level comparisons of H2A and H2B forms with bilaterian counterparts suggest the possibility of a highly mobile nature of nucleosomes in hydra. Absolute quantitation of transcripts confirmed the high copy number of histones and supported the canonical nature of H2A. Furthermore, functional characterization of H2A.X.1 and a unique variant H2A.X.2 in the gastric region suggest their role in the maintenance of genome integrity and differentiation processes. These findings provide insights into the evolution of histones and their variants in hydra. Copyright © 2017 Elsevier GmbH. All rights reserved.

  19. Cylinder Symmetric Measures with the Tail Property

    NARCIS (Netherlands)

    Balkema, A.A.

    2006-01-01

    Abstract: A Pareto distribution has the property that any tail of the distribution has the same shape as the original distribution. The exponential distribution and the uniform distribution have the tail property too. The tail property characterizes the univariate generalized Pareto distributions.

  20. 14 CFR 29.1565 - Tail rotor.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Tail rotor. 29.1565 Section 29.1565 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS....1565 Tail rotor. Each tail rotor must be marked so that its disc is conspicuous under normal daylight...

  1. 14 CFR 27.1565 - Tail rotor.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Tail rotor. 27.1565 Section 27.1565 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... Tail rotor. Each tail rotor must be marked so that its disc is conspicuous under normal daylight ground...

  2. Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts.

    Science.gov (United States)

    Schuetze, Katherine B; Stratton, Matthew S; Blakeslee, Weston W; Wempe, Michael F; Wagner, Florence F; Holson, Edward B; Kuo, Yin-Ming; Andrews, Andrew J; Gilbert, Tonya M; Hooker, Jacob M; McKinsey, Timothy A

    2017-04-01

    Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly affect cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II, and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiologic and pathophysiological processes. For example, the benzamide class I HDAC-selective inhibitor, MGCD0103 [N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide], was shown to block cardiac fibrosis, a process involving excess extracellular matrix deposition, which often results in heart dysfunction. Here, we compare the mechanisms of action of structurally distinct HDAC inhibitors in isolated primary cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart. TSA, MGCD0103, and the cyclic peptide class I HDAC inhibitor, apicidin, exhibited a common ability to enhance histone acetylation, and all potently blocked cardiac fibroblast cell cycle progression. In contrast, MGCD0103, but not TSA or apicidin, paradoxically increased expression of a subset of fibrosis-associated genes. Using the cellular thermal shift assay, we provide evidence that the divergent effects of HDAC inhibitors on cardiac fibroblast gene expression relate to differential engagement of HDAC1- and HDAC2-containing complexes. These findings illustrate the importance of employing multiple compounds when pharmacologically assessing HDAC function in a cellular context and during HDAC inhibitor drug development. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Effects of nickel, chromate, and arsenite on histone 3 lysine methylation.

    Science.gov (United States)

    Zhou, Xue; Li, Qin; Arita, Adriana; Sun, Hong; Costa, Max

    2009-04-01

    Occupational exposure to nickel (Ni), chromium (Cr), and arsenic (As) containing compounds has been associated with lung cancer and other adverse health effects. Their carcinogenic properties may be attributable in part, to activation and/or repression of gene expression induced by changes in the DNA methylation status and histone tail post-translational modifications. Here we show that individual treatment with nickel, chromate, and arsenite all affect the gene activating mark H3K4 methylation. We found that nickel (1 mM), chromate (10 microM), and arsenite (1 microM) significantly increase tri-methyl H3K4 after 24 h exposure in human lung carcinoma A549 cells. Seven days of exposure to lower levels of nickel (50 and 100 microM), chromate (0.5 and 1 microM) or arsenite (0.1, 0.5 and 1 microM) also increased tri-methylated H3K4 in A549 cells. This mark still remained elevated and inherited through cell division 7 days following removal of 1 microM arsenite. We also demonstrate by dual staining immunofluorescence microscopy that both H3K4 tri-methyl and H3K9 di-methyl marks increase globally after 24 h exposure to each metal treatment in A549 cells. However, the tri-methyl H3K4 and di-methyl H3K9 marks localize in different regions in the nucleus of the cell. Thus, our study provides further evidence that a mechanism(s) of carcinogenicity of nickel, chromate, and arsenite metal compounds may involve alterations of various histone tail modifications that may in turn affect the expression of genes that may cause transformation.

  4. Effects of Nickel, Chromate, and Arsenite on Histone 3 Lysine Methylation

    Science.gov (United States)

    Zhou, Xue; Li, Qin; Arita, Adriana; Sun, Hong; Costa, Max

    2009-01-01

    Occupational exposure to nickel(Ni), chromium(Cr), and arsenic(As) containing compounds has been associated with lung cancer and other adverse health effects. Their carcinogenic properties may be attributable in part, to activation and/or repression of gene expression induced by changes in the DNA methylation status and histone tail post-translational modifications. Here we show that individual treatment with nickel, chromate, and arsenite all affect the gene activating mark H3K4 methylation. We found that nickel(1 mM), chromate(10 μM), and arsenite(1 μM) significantly increase tri-methyl H3K4 after 24 h exposure in human lung carcinoma A549 cells. Seven days of exposure to lower levels of nickel(50 and 100 μM), chromate(0.5 and 1 μM) or arsenite(0.1 0.5 and 1 μM) also increased tri-methylated H3K4 in A549 cells. This mark still remained elevated and inherited through cell division seven days following removal of 1 μM arsenite. We also demonstrate by dual staining immunofluorescence microscopy that both H3K4 tri-methyl and H3K9 di-methyl marks increase globally after 24 h exposure to each metal treatment in A549 cells. However, the tri-methyl H3K4 and di-methyl H3K9 marks localize in different regions in the nucleus of the cell. Thus, our study provides further evidence that a mechanism(s) of carcinogenicity of nickel, chromate, and arsenite metal compounds may involve alterations of various histone tail modifications that may in turn affect the expression of genes that may cause transformation. PMID:19371620

  5. Effects of tail docking and docking length on neuroanatomical changes in healed tail tips of pigs

    DEFF Research Database (Denmark)

    Herskin, M. S.; Thodberg, K.; Jensen, Henrik Elvang

    2015-01-01

    In pig production, piglets are tail docked at birth in order to prevent tail biting later in life. In order to examine the effects of tail docking and docking length on the formation of neuromas, we used 65 pigs and the following four treatments: intact tails (n=18); leaving 75% (n=17); leaving 5...

  6. Histone Variant Regulates DNA Repair via Chromatin Condensation | Center for Cancer Research

    Science.gov (United States)

    Activating the appropriate DNA repair pathway is essential for maintaining the stability of the genome after a break in both strands of DNA. How a pathway is selected, however, is not well understood. Since these double strand breaks (DSBs) occur while DNA is packaged as chromatin, changes in its organization are necessary for repair to take place. Numerous alterations have been associated with DSBs, including modifications of histone tails and exchange of histone variants, some increasing chromatin accessibility, others reducing it. In fact, distinct domains flanking a single DSB have been observed that are bound by opposing repair pathway proteins 53BP1and BRCA1, which promote non-homologous end joining (NHEJ) and homologous recombination (HR), respectively. To investigate whether DSB-proximal chromatin reorganization affects repair pathway selection, Philipp Oberdoerffer, Ph.D., of CCR’s Laboratory of Receptor Biology and Gene Expression, and his colleagues performed a high-throughput RNA interference (RNAi) screen for chromatin-related genes that modulate HR.

  7. BRCA1 Is a Histone-H2A-Specific Ubiquitin Ligase

    Directory of Open Access Journals (Sweden)

    Reinhard Kalb

    2014-08-01

    Full Text Available The RING domain proteins BRCA1 and BARD1 comprise a heterodimeric ubiquitin (E3 ligase that is required for the accumulation of ubiquitin conjugates at sites of DNA damage and for silencing at DNA satellite repeat regions. Despite its links to chromatin, the substrate and underlying function of the BRCA1/BARD1 ubiquitin ligase remain unclear. Here, we show that BRCA1/BARD1 specifically ubiquitylates histone H2A in its C-terminal tail on lysines 127 and 129 in vitro and in vivo. The specificity for K127-129 is acquired only when H2A is within a nucleosomal context. Moreover, site-specific targeting of the BRCA1/BARD1 RING domains to chromatin is sufficient for H2Aub foci formation in vivo. Our data establish BRCA1/BARD1 as a histone-H2A-specific E3 ligase, helping to explain its localization and activities on chromatin in cells.

  8. Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis.

    Science.gov (United States)

    Govin, Jérôme; Dorsey, Jean; Gaucher, Jonathan; Rousseaux, Sophie; Khochbin, Saadi; Berger, Shelley L

    2010-08-15

    Profound epigenetic differences exist between genomes derived from male and female gametes; however, the nature of these changes remains largely unknown. We undertook a systematic investigation of chromatin reorganization during gametogenesis, using the model eukaryote Saccharomyces cerevisiae to examine sporulation, which has strong similarities with higher eukaryotic spermatogenesis. We established a mutational screen of histones H3 and H4 to uncover substitutions that reduce sporulation efficiency. We discovered two patches of residues-one on H3 and a second on H4-that are crucial for sporulation but not critical for mitotic growth, and likely comprise interactive nucleosomal surfaces. Furthermore, we identified novel histone post-translational modifications that mark the chromatin reorganization process during sporulation. First, phosphorylation of H3T11 appears to be a key modification during meiosis, and requires the meiotic-specific kinase Mek1. Second, H4 undergoes amino tail acetylation at Lys 5, Lys 8, and Lys 12, and these are synergistically important for post-meiotic chromatin compaction, occurring subsequent to the post-meiotic transient peak in phosphorylation at H4S1, and crucial for recruitment of Bdf1, a bromodomain protein, to chromatin in mature spores. Strikingly, the presence and temporal succession of the new H3 and H4 modifications are detected during mouse spermatogenesis, indicating that they are conserved through evolution. Thus, our results show that investigation of gametogenesis in yeast provides novel insights into chromatin dynamics, which are potentially relevant to epigenetic modulation of the mammalian process.

  9. histoneHMM : Differential analysis of histone modifications with broad genomic footprints

    NARCIS (Netherlands)

    Heinig, Matthias; Colomé-Tatché, Maria; Taudt, Aaron; Rintisch, Carola; Schafer, Sebastian; Pravenec, Michal; Hubner, Norbert; Vingron, Martin; Johannes, Frank

    2015-01-01

    Background: ChIP-seq has become a routine method for interrogating the genome-wide distribution of various histone modifications. An important experimental goal is to compare the ChIP-seq profiles between an experimental sample and a reference sample, and to identify regions that show differential

  10. Histone Crosstalk between H3S10ph and H4K16ac Generates a Histone Code that Mediates Transcription Elongation

    National Research Council Canada - National Science Library

    Zippo, Alessio; Serafini, Riccardo; Rocchigiani, Marina; Pennacchini, Susanna; Krepelova, Anna; Oliviero, Salvatore

    2009-01-01

    .... This model is based on the histone code hypothesis, where specific histone modifications, acting alone or in combination, can promote or inhibit the binding of a protein (the “reader”) to the nucleosome ( Strahl and Allis, 2000 ). The reader can promote a second histone modification, determining a histone crosstalk which generates a different binding platform ...

  11. Chemical Probes of Histone Lysine Methyltransferases

    Science.gov (United States)

    2015-01-01

    Growing evidence suggests that histone methyltransferases (HMTs, also known as protein methyltransferases (PMTs)) play an important role in diverse biological processes and human diseases by regulating gene expression and the chromatin state. Therefore, HMTs have been increasingly recognized by the biomedical community as a class of potential therapeutic targets. High quality chemical probes of HMTs, as tools for deciphering their physiological functions and roles in human diseases and testing therapeutic hypotheses, are critical for advancing this promising field. In this review, we focus on the discovery, characterization, and biological applications of chemical probes for HMTs. PMID:25423077

  12. Histone Deacetylase: Therapeutic Targets in Retinal Degeneration.

    Science.gov (United States)

    Daly, Conor; Yin, Jun; Kennedy, Breandán N

    2016-01-01

    Previous studies report that retinitis pigmentosa (RP) patients treated with the histone deacetylase inhibitor (HDACi) valproic acid (VPA) present with improved visual fields and delayed vision loss. However, other studies report poor efficacy and safety of HDACi in other cohorts of retinal degeneration patients. Furthermore, the molecular mechanisms by which HDACi can improve visual function is unknown, albeit HDACi can attenuate pro-apoptotic stimuli and induce expression of neuroprotective factors. Thus, further analysis of HDACi is warranted in pre-clinical models of retinal degeneration including zebrafish. Analysis of HDAC expression in developing zebrafish reveals diverse temporal expression patterns during development and maturation of visual function.

  13. Extracting aluminum from dross tailings

    Science.gov (United States)

    Amer, A. M.

    2002-11-01

    Aluminum dross tailings, an industrial waste, from the Egyptian Aluminium Company (Egyptalum) was used to produce two types of alums: aluminum-sulfate alum [itAl2(SO4)3.12H2O] and ammonium-aluminum alum [ (NH 4)2SO4AL2(SO4)3.24H2O]. This was carried out in two processes. The first process is leaching the impurities using diluted H2SO4 with different solid/liquid ratios at different temperatures to dissolve the impurities present in the starting material in the form of solute sulfates. The second process is the extraction of aluminum (as aluminum sulfate) from the purifi ed aluminum dross tailings thus produced. The effects of temperature, time of reaction, and acid concentration on leaching and extraction processes were studied. The product alums were analyzed using x-ray diffraction and thermal analysis techniques.

  14. MESSENGER Observations of Extreme Loading and Unloading of Mercury's Magnetic Tail

    Science.gov (United States)

    Slavin, James A.; Anderson, Brian J.; Baker, Daniel N.; Benna, Mehdi; Boardsen, Scott A.; Gloeckler, George; Gold, Robert E.; Ho, George C.; Korth, Haje; Krimigis, Stamatios M.; hide

    2010-01-01

    During MESSENGER's third flyby of Mercury, the magnetic field in the planet's magnetotail increased by factors of 2 to 3.5 over intervals of 2 to 3 min. Magnetospheric substorms at Earth are powered by similar tail loading, but the amplitude is approx.10 times less and typical durations are approx.1 hour. The extreme tail loading observed at Mercury implies that the relative intensity of sub storms must be much larger than at Earth. The correspondence between the duration of tail field enhancements and the characteristic time for the Dungey cycle, which describes plasma circulation through Mercury's magnetosphere. suggests that such circulation determines substorm timescale. A key aspect of tail unloading during terrestrial substorms is the acceleration of energetic charged particles, but no acceleration signatures were seen during the MESSENGER flyby.

  15. Origin of the tail in Green's functions in odd-dimensional space-times

    Science.gov (United States)

    Dai, De-Chang; Stojkovic, Dejan

    2013-10-01

    It is well known that the scalar field Green's function in odd dimensions has a tail, i.e. a non-zero support inside the light cone, which in turn implies that the Huygens' principle is violated. However, the reason behind this behavior is still not quite clear. In this paper we shed more light on the physical origin of the tail by regularizing the term which is usually ignored in the literature since it vanishes due to the action of the delta function. With this extra term the Green's function does not satisfy the source-free wave equation (in the region outside of the source). We show that this term corresponds to a charge imprinted on the light-cone shell. Unlike the vector field charge, a moving scalar field charge is not Lorentz invariant and is contracted by a factor. If a scalar charge is moving at the speed of light, it appears to be zero in the static (with respect to the original physical charge) observer's frame. However, the field it sources is not entirely on the light cone. Thus, it is likely that this hidden charge sources the mysterious tail in odd dimensions.

  16. Definition of topological susceptibility via lattice anomalous Ward identities and its perturbative tail

    Energy Technology Data Exchange (ETDEWEB)

    Bochicchio, M.

    1984-09-01

    The lattice definition of topological charge density suggested by the U(1)A anomalous Ward identity is considered. It is proved that the associated topological susceptibility has no perturbative tail in the chiral limit (zero renormalized quark mass) by studying the infrared properties of perturbative lattice QCD.

  17. On the definition of topological susceptibility via lattice-anomalous ward identities and its perturbative tail

    Energy Technology Data Exchange (ETDEWEB)

    Bochicchio, M.

    1986-07-07

    We consider the lattice definition of the topological charge density suggested by the U(1)sub(A) anomalous Ward identity. We prove that the associated topological susceptibility has no perturbative tail in the ''chiral limit'' (zero renormalized quark mass) by studying the infrared properties of perturbative lattice QCD.

  18. Space charge

    CERN Document Server

    Schindl, Karlheinz

    2005-01-01

    The Coulomb forces between the charged particles of a high-intensity beam in an accelerator create a self-field which acts on the particles inside the beam like a distributed lens, defocusing in both transverse planes. A beam moving with speed n is accompanied by a magnetic field which partially cancels the electrostatic defocusing effect, with complete cancellation at c, the speed of light. The effect of this 'direct space charge' is evaluated for transport lines and synchrotrons where the number of betatron oscillations per machine turn, Q, is reduced by DQ. In a real accelerator, the beam is also influenced by the environment (beam pipe, magnets, etc.) which generates 'indirect' space charge effects. For a smooth and perfectly conducting wall, they can easily be evaluated by introducing image charges and currents. These 'image effects' do not cancel when n approaches c, thus they become dominant for high-energy synchrotrons. Each particle in the beam has its particular incoherent tune Q and incoherent tune...

  19. Resolving Heart Regeneration by Replacement Histone Profiling.

    Science.gov (United States)

    Goldman, Joseph Aaron; Kuzu, Guray; Lee, Nutishia; Karasik, Jaclyn; Gemberling, Matthew; Foglia, Matthew J; Karra, Ravi; Dickson, Amy L; Sun, Fei; Tolstorukov, Michael Y; Poss, Kenneth D

    2017-02-27

    Chromatin regulation is a principal mechanism governing animal development, yet it is unclear to what extent structural changes in chromatin underlie tissue regeneration. Non-mammalian vertebrates such as zebrafish activate cardiomyocyte (CM) division after tissue damage to regenerate lost heart muscle. Here, we generated transgenic zebrafish expressing a biotinylatable H3.3 histone variant in CMs and derived cell-type-specific profiles of histone replacement. We identified an emerging program of putative enhancers that revise H3.3 occupancy during regeneration, overlaid upon a genome-wide reduction of H3.3 from promoters. In transgenic reporter lines, H3.3-enriched elements directed gene expression in subpopulations of CMs. Other elements increased H3.3 enrichment and displayed enhancer activity in settings of injury- and/or Neuregulin1-elicited CM proliferation. Dozens of consensus sequence motifs containing predicted transcription factor binding sites were enriched in genomic regions with regeneration-responsive H3.3 occupancy. Thus, cell-type-specific regulatory programs of tissue regeneration can be revealed by genome-wide H3.3 profiling. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Histone Methylation and Epigenetic Silencing in Breast Cancer

    Science.gov (United States)

    2011-02-01

    methylation of histone H1 or nucleosomal histone H3, Mol. Cell 14 (2004) 183–193. [64] C. Martin , R. Cao, Y. Zhang, Substrate preferences of the EZH2...101] N.A. Lobo , Y. Shimono, D. Qian, M.F. Clarke, The biology of cancer stem cells, Annu. Rev. Cell Dev. Biol. 23 (2007) 675–699. [102] J. Stingl, C

  1. A Peek into the Complex Realm of Histone Phosphorylation▿

    Science.gov (United States)

    Banerjee, Taraswi; Chakravarti, Debabrata

    2011-01-01

    Although discovered long ago, posttranslational phosphorylation of histones has been in the spotlight only recently. Information is accumulating almost daily on phosphorylation of histones and their roles in cellular physiology and human diseases. An extensive cross talk exists between phosphorylation and other posttranslational modifications, which together regulate various biological processes, including gene transcription, DNA repair, and cell cycle progression. Recent research on histone phosphorylation has demonstrated that nearly all histone types are phosphorylated at specific residues and that these modifications act as a critical intermediate step in chromosome condensation during cell division, transcriptional regulation, and DNA damage repair. As with all young fields, apparently conflicting and sometimes controversial observations about histone phosphorylations and their true functions in different species are found in the literature. Accumulating evidence suggests that instead of functioning strictly as part of a general code, histone phosphorylation probably functions by establishing cross talk with other histone modifications and serving as a platform for recruitment or release of effector proteins, leading to a downstream cascade of events. Here we extensively review published information on the complexities of histone phosphorylation, the roles of proteins recognizing these modifications and the resuting physiological outcome, and, importantly, future challenges and opportunities in this fast-moving field. PMID:22006017

  2. Evidence for sequence biases associated with patterns of histone methylation

    Directory of Open Access Journals (Sweden)

    Wang Zhong

    2012-08-01

    Full Text Available Abstract Background Combinations of histone variants and modifications, conceptually representing a histone code, have been proposed to play a significant role in gene regulation and developmental processes in complex organisms. While various mechanisms have been implicated in establishing and maintaining epigenetic patterns at specific locations in the genome, they are generally believed to be independent of primary DNA sequence on a more global scale. Results To address this systematically in the case of the human genome, we have analyzed primary DNA sequences underlying patterns of 19 different methylated histones in human primary T-cells and patterns of three methylated histones across additional human cell lines. We report strong sequence biases associated with most of these histone marks genome-wide in each cell type. Furthermore, the sequence characteristics for such association are distinct for different groups of histone marks. Conclusions These findings provide evidence of an influence of genomic sequence on patterns of histone modification associated with gene expression and chromatin programming, and they suggest that the mechanisms responsible for global histone modifications may interpret genomic sequence in various ways.

  3. Histone methylation and aging: Lessons learned from model systems

    Science.gov (United States)

    McCauley, Brenna S.; Dang, Weiwei

    2014-01-01

    Aging induces myriad cellular and, ultimately, physiological changes that cause a decline in an organism's functional capabilities. Although the aging process and pathways that regulate it have been extensively studied, only in the last decade have we begun to appreciate that dynamic histone methylation may contribute to this process. In this review, we discuss recent work implicating histone methylation in aging. Loss of certain histone methyltransferases and demethylases changes lifespan in invertebrates, and alterations in histone methylation in aged organisms regulate lifespan and aging phenotypes, including oxidative stress-induced hormesis in yeast, insulin signaling in Caenorhabiditis elegans and mammals, and the senescence-associated secretory phenotype in mammals. In all cases where histone methylation has been shown to impact aging and aging phenotypes, it does so by regulating transcription, suggesting that this is a major mechanism of its action in this context. Histone methylation additionally regulates or is regulated by other cellular pathways that contribute to or combat aging. Given the numerous processes that regulate aging and histone methylation, and are in turn regulated by them, the role of histone methylation in aging is almost certainly underappreciated. PMID:24859460

  4. Co-regulation of histone-modifying enzymes in cancer.

    Directory of Open Access Journals (Sweden)

    Abul B M M K Islam

    Full Text Available Cancer is characterized by aberrant patterns of expression of multiple genes. These major shifts in gene expression are believed to be due to not only genetic but also epigenetic changes. The epigenetic changes are communicated through chemical modifications, including histone modifications. However, it is unclear whether the binding of histone-modifying proteins to genomic regions and the placing of histone modifications efficiently discriminates corresponding genes from the rest of the genes in the human genome. We performed gene expression analysis of histone demethylases (HDMs and histone methyltransferases (HMTs, their target genes and genes with relevant histone modifications in normal and tumor tissues. Surprisingly, this analysis revealed the existence of correlations in the expression levels of different HDMs and HMTs. The observed HDM/HMT gene expression signature was specific to particular normal and cancer cell types and highly correlated with target gene expression and the expression of genes with histone modifications. Notably, we observed that trimethylation at lysine 4 and lysine 27 separated preferentially expressed and underexpressed genes, which was strikingly different in cancer cells compared to normal cells. We conclude that changes in coordinated regulation of enzymes executing histone modifications may underlie global epigenetic changes occurring in cancer.

  5. The Fork in the Road: Histone Partitioning During DNA Replication

    Directory of Open Access Journals (Sweden)

    Anthony T. Annunziato

    2015-06-01

    Full Text Available In the following discussion the distribution of histones at the replication fork is examined, with specific attention paid to the question of H3/H4 tetramer "splitting." After a presentation of early experiments surrounding this topic, more recent contributions are detailed. The implications of these findings with respect to the transmission of histone modifications and epigenetic models are also addressed.

  6. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease

    DEFF Research Database (Denmark)

    Cloos, Paul A C; Christensen, Jesper; Agger, Karl

    2008-01-01

    The enzymes catalyzing lysine and arginine methylation of histones are essential for maintaining transcriptional programs and determining cell fate and identity. Until recently, histone methylation was regarded irreversible. However, within the last few years, several families of histone...... demethylases erasing methyl marks associated with gene repression or activation have been identified, underscoring the plasticity and dynamic nature of histone methylation. Recent discoveries have revealed that histone demethylases take part in large multiprotein complexes synergizing with histone deacetylases......, histone methyltransferases, and nuclear receptors to control developmental and transcriptional programs. Here we review the emerging biochemical and biological functions of the histone demethylases and discuss their potential involvement in human diseases, including cancer....

  7. Single-Bunch Stability With Direct Space Charge

    CERN Multimedia

    Oeftiger, Adrian

    2017-01-01

    Previous studies have shown the suppressing effect of direct space charge on impedance-driven head-tail instabilities. The present work investigates transverse stability for the HL-LHC scenario based on our macro-particle simulation tool PyHEADTAIL using realistic bunch distributions. The impact of selfconsistent modelling is briefly discussed for non-linear space charge forces. We study how space charge pushes the instability threshold for the transverse mode coupling instability (TMCI) occurring between mode 0 and -1. Next we consider finite chromaticity: in absence of space charge, the impedance model predicts head-tail instabilities. For a selected case below TMCI threshold at Q0 = 5, we demonstrate the stabilising effect of space charge. Finally, we compare simulation results to past LHC measurements.

  8. Acetyl-CoA carboxylase regulates global histone acetylation.

    Science.gov (United States)

    Galdieri, Luciano; Vancura, Ales

    2012-07-06

    Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment. However, because nucleocytosolic acetyl-CoA is also used for de novo synthesis of fatty acids, histone acetylation and synthesis of fatty acids compete for the same acetyl-CoA pool. The first and rate-limiting reaction in de novo synthesis of fatty acids is carboxylation of acetyl-CoA to form malonyl-CoA, catalyzed by acetyl-CoA carboxylase. In yeast Saccharomyces cerevisiae, acetyl-CoA carboxylase is encoded by the ACC1 gene. In this study, we show that attenuated expression of ACC1 results in increased acetylation of bulk histones, globally increased acetylation of chromatin histones, and altered transcriptional regulation. Together, our data indicate that Acc1p activity regulates the availability of acetyl-CoA for histone acetyltransferases, thus representing a link between intermediary metabolism and epigenetic mechanisms of transcriptional regulation.

  9. The premelting of nucleoprotein: role of non-histone proteins

    Science.gov (United States)

    Wilhelm, F.Xavier; De Murcia, Gilbert M.; Daune, Michel P.

    1974-01-01

    In native nucleoprotein, the premelting structural changes of DNA are not observed by circular dichroism measurements. In order to determine which protein fraction of chromatin is responsible for the absence of premelting we have examined a series of nucleoproteins depleted of different protein fractions by treatment with sodium chloride or sodium deoxycholate. The premelting reappears as soon as non-histone proteins are removed or in residual complexes from which the two slightly lysine-rich histone fractions (F2a2+F2b) have been removed. On the other hand, it is shown that histone F1 alone is not able to suppress the premelting phenomenon. It is thus concluded that the absence of premelting is a property of native nucleoprotein where interactions between the different proteins complexed with DNA can occur and especially between the non-histone proteins and the two slightly lysine-rich histone fractions. PMID:10793734

  10. Epigenetic regulation of motivated behaviors by histone deacetylase inhibitors.

    Science.gov (United States)

    Elvir, Lindsay; Duclot, Florian; Wang, Zuoxin; Kabbaj, Mohamed

    2017-10-08

    Growing evidence has begun to elucidate the contribution of epigenetic mechanisms in the modulation and maintenance of gene expression and behavior. Histone acetylation is one such epigenetic mechanism, which has been shown to profoundly alter gene expression and behaviors. In this review, we begin with an overview of the major epigenetic mechanisms including histones acetylation. We next focus on recent evidence about the influence of environmental stimuli on various motivated behaviors through histone acetylation and highlight how histone deacetylase inhibitors can correct some of the pathologies linked to motivated behaviors including substance abuse, feeding and social attachments. Particularly, we emphasize that the effects of histone deacetylase inhibitors on motivated behaviors are time and context-dependent. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Finding combinatorial histone code by semi-supervised biclustering

    Directory of Open Access Journals (Sweden)

    Teng Li

    2012-07-01

    Full Text Available Abstract Background Combinatorial histone modification is an important epigenetic mechanism for regulating chromatin state and gene expression. Given the rapid accumulation of genome-wide histone modification maps, there is a pressing need for computational methods capable of joint analysis of multiple maps to reveal combinatorial modification patterns. Results We present the Semi-Supervised Coherent and Shifted Bicluster Identification algorithm (SS-CoSBI. It uses prior knowledge of combinatorial histone modifications to guide the biclustering process. Specifically, co-occurrence frequencies of histone modifications characterized by mass spectrometry are used as probabilistic priors to adjust the similarity measure in the biclustering process. Using a high-quality set of transcriptional enhancers and associated histone marks, we demonstrate that SS-CoSBI outperforms its predecessor by finding histone modification and genomic locus biclusters with higher enrichment of enhancers. We apply SS-CoSBI to identify multiple cell-type-specific combinatorial histone modification states associated with human enhancers. We show enhancer histone modification states are correlated with the expression of nearby genes. Further, we find that enhancers with the histone mark H3K4me1 have higher levels of DNA methylation and decreased expression of nearby genes, suggesting a functional interplay between H3K4me1 and DNA methylation that can modulate enhancer activities. Conclusions The analysis presented here provides a systematic characterization of combinatorial histone codes of enhancers across three human cell types using a novel semi-supervised biclustering algorithm. As epigenomic maps accumulate, SS-CoSBI will become increasingly useful for understanding combinatorial chromatin modifications by taking advantage of existing knowledge. Availability and implementation SS-CoSBI is implemented in C. The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/SS-CoSBI.gz.

  12. Finding combinatorial histone code by semi-supervised biclustering.

    Science.gov (United States)

    Teng, Li; Tan, Kai

    2012-07-03

    Combinatorial histone modification is an important epigenetic mechanism for regulating chromatin state and gene expression. Given the rapid accumulation of genome-wide histone modification maps, there is a pressing need for computational methods capable of joint analysis of multiple maps to reveal combinatorial modification patterns. We present the Semi-Supervised Coherent and Shifted Bicluster Identification algorithm (SS-CoSBI). It uses prior knowledge of combinatorial histone modifications to guide the biclustering process. Specifically, co-occurrence frequencies of histone modifications characterized by mass spectrometry are used as probabilistic priors to adjust the similarity measure in the biclustering process. Using a high-quality set of transcriptional enhancers and associated histone marks, we demonstrate that SS-CoSBI outperforms its predecessor by finding histone modification and genomic locus biclusters with higher enrichment of enhancers. We apply SS-CoSBI to identify multiple cell-type-specific combinatorial histone modification states associated with human enhancers. We show enhancer histone modification states are correlated with the expression of nearby genes. Further, we find that enhancers with the histone mark H3K4me1 have higher levels of DNA methylation and decreased expression of nearby genes, suggesting a functional interplay between H3K4me1 and DNA methylation that can modulate enhancer activities. The analysis presented here provides a systematic characterization of combinatorial histone codes of enhancers across three human cell types using a novel semi-supervised biclustering algorithm. As epigenomic maps accumulate, SS-CoSBI will become increasingly useful for understanding combinatorial chromatin modifications by taking advantage of existing knowledge. SS-CoSBI is implemented in C. The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/SS-CoSBI.gz.

  13. CTCF induces histone variant incorporation, erases the H3K27me3 histone mark and opens chromatin

    NARCIS (Netherlands)

    O. Weth (Oliver); C. Paprotka (Christine); K. Günther (Katharina); A. Schulte (Astrid); M. Baierl (Manuel); J. Leers (Joerg); N.J. Galjart (Niels); R. Renkawitz (Rainer)

    2014-01-01

    textabstractInsulators functionally separate active chromatin domains frominactive ones. The insulator factor, CTCF, has been found to bind to boundaries and to mediate insulator function. CTCF binding sites are depleted for the histone modification H3K27me3 and are enriched for the histone variant

  14. On the classification of comet plasma tails

    Science.gov (United States)

    Mozhenkov, E. R.; Vaisberg, O. L.

    2017-07-01

    The investigation of plasma tails of comets is an important part of comet research. Different classifications of plasma tails of comets are proposed. Plasma acceleration in the tails is investigated in sufficient detail. Several cometary forms are explained. Plasma tails of Mars and Venus were observed during the first studies of these planets. They are associated with the capture of ionized atoms and exosphere molecules by the solar wind magnetized plasma flow. Distinct plasma tails of Mars and Venus are caused by the mass loading of the solar wind with heavy ions. It was shown that the transverse dimension of the tails of Mars, Venus, and comets can be quite accurately determined by production rate of the obstacle to the solar wind flow. While plasma tails of Mars and Venus are investigated by in situ measurements from spacecraft, observations of comet tails from the Earth make it possible to see the entire object under study and to monitor changes in its structure. A certain similarity of cometary and planetary tails can be explained by the nonmagnetic nature of both types of bodies. Thus, it is reasonable to suppose that investigations of plasma tails of comets can supplement the information obtained by in situ methods of the study of the planets. In this paper, plasma tails of comets, presumably analogous to the plasma tails of Mars and Venus, have been identified on modern photographs of comets (more than 1500 photographs viewed). Only quasi-steady laminar tails are considered. They are divided into two types: double structures and outflows. The paper attempts to define the 3D structure of double structures and to determine certain characteristics of outflows.

  15. Combined Triplex/Duplex Invasion of Double-Stranded DNA by "Tail-Clamp" Peptide Nucleic Acid

    DEFF Research Database (Denmark)

    Bentin, Thomas; Larsen, H. J.; Nielsen, Peter E.

    2003-01-01

    as determined by T-m measurements. Binding to double-stranded (ds) DNA occurred by combined triplex and duplex invasion as analyzed by permanganate probing. Furthermore, C-50 measurements revealed that tail-clamp PNAs consistently bound the dsDNA target more efficiently, and kinetics experiments revealed......"Tail-clamp" PNAs composed of a short (hexamer) homopyrimidine triplex forming domain and a (decamer) mixed sequence duplex forming extension have been designed. Tail-clamp PNAs display significantly increased binding to single-stranded DNA compared with PNAs lacking a duplex-forming extension...... that this was due to a dramatically reduced dissociation rate of such complexes. Increasing the PNA net charge also increased binding efficiency, but unexpectedly, this increase was much more pronounced for tailless-clamp PNAs than for tail-clamp PNAs. Finally, shortening the tail-clamp PNA triplex invasion moiety...

  16. The ATAD2 bromodomain binds different acetylation marks on the histone H4 in similar fuzzy complexes.

    Science.gov (United States)

    Langini, Cassiano; Caflisch, Amedeo; Vitalis, Andreas

    2017-10-06

    Bromodomains are protein modules adopting conserved helix bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders. To interfere with or modulate these processes, it is therefore of fundamental interest to understand the molecular mechanisms by which epigenetic regulation occurs. Here, we present results from molecular dynamics simulations of a doubly acetylated histone H4 peptide bound to the bromodomain of ATAD2 (hereafter referred to as ATAD2A). These simulations revealed how the flexibility of ATAD2A's major loop, the so-called ZA loop, creates an adaptable interface that preserves the disorder of both peptide and loop in the bound state. We further demonstrate that the binding involves an almost identical average pattern of interactions irrespective of which acetyl mark is inserted into the pocket. In conjunction with a likely mechanism of electrostatically driven recruitment, our simulation results highlight how the bromodomain is built toward promiscuous binding with low specificity. In conclusion, the simulations indicate that disorder and electrostatic steering function jointly to recruit ATAD2A to the histone core and that these fuzzy interactions may promote cooperativity between nearby epigenetic marks. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children.

    Science.gov (United States)

    Lee, Julieann; Solomon, David A; Tihan, Tarik

    2017-03-01

    Genetic profiling is an increasingly useful tool for sub-classification of gliomas in adults and children. Specific gene mutations, structural rearrangements, DNA methylation patterns, and gene expression profiles are now recognized to define molecular subgroups of gliomas that arise in distinct anatomic locations and patient age groups, and also provide a better prediction of clinical outcomes for glioma patients compared to histologic assessment alone. Understanding the role of these distinctive genetic alterations in gliomagenesis is also important for the development of potential targeted therapeutic interventions. Mutations including K27M and G34R/V that affect critical amino acids within the N-terminal tail of the histone H3 variants, H3.3 and H3.1 (encoded by H3F3A and HIST1H3B genes), are prime examples of mutations in diffuse gliomas with characteristic clinical associations that can help diagnostic classification and guide effective patient management. These histone H3 mutations frequently co-occur with inactivating mutations in ATRX in association with alternative lengthening of telomeres. Telomere length can also be maintained through upregulation of telomerase reverse transcriptase (TERT) expression driven by mutation within the TERT gene promoter region, an alteration most commonly found in oligodendrogliomas and primary glioblastomas arising in adults. Interestingly, the genetic alterations perturbing histone and telomere function in pediatric gliomas tend to be different from those present in adult tumors. We present a review of these mutations affecting the histone code and telomere length, highlighting their importance in prognosis and as targets for novel therapeutics in the treatment of diffuse gliomas.

  18. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells.

    Directory of Open Access Journals (Sweden)

    Yutaka Kondo

    Full Text Available BACKGROUND: Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. However, the functional roles of the histone methyltransferases (HMT in cancer remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We studied RNAi-based inhibition (knockdown, KD of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102 in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD cells. CONCLUSIONS/SIGNIFICANCE: These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers.

  19. Microbially-accelerated consolidation of oil sands tailings. Pathway I: changes in porewater chemistry

    Directory of Open Access Journals (Sweden)

    Tariq eSiddique

    2014-03-01

    Full Text Available Dispersed clay particles in mine tailings and soft sediments remain suspended for decades, hindering consolidation and challenging effective management of these aqueous slurries. Current geotechnical engineering models of self-weight consolidation of tailings do not consider microbial contribution to sediment behavior, however, here we show that microorganisms indigenous to oil sands tailings change the porewater chemistry and accelerate consolidation of oil sands tailings. A companion paper describes the role of microbes in alteration of clay chemistry in tailings. Microbial metabolism in mature fine tailings (MFT amended with an organic substrate (hydrolyzed canola meal produced methane (CH4 and carbon dioxide (CO2. Dissolution of biogenic CO2 lowered the pH of amended MFT to pH 6.4 versus unamended MFT (pH 7.7. About 12% more porewater was recovered from amended than unamended MFT during 2 months of active microbial metabolism, concomitant with consolidation of tailings. The lower pH in amended MFT dissolved carbonate minerals, thereby releasing divalent cations including calcium (Ca2+ and magnesium (Mg2+ and increasing bicarbonate (HCO3- in porewater. The higher concentrations increased the ionic strength of the porewater, in turn reducing the thickness of the diffuse double layer (DDL of clay particles by reducing the surface charge potential (repulsive forces of the clay particles. The combination of these processes accelerated consolidation of oil sands tailings. In addition, ebullition of biogenic gases created transient physical channels for release of porewater. In contrast, saturating the MFT with non-biogenic CO2 had little effect on consolidation. These results have significant implications for management and reclamation of oil sands tailings ponds and broad importance in anaerobic environments such as contaminated harbors and estuaries containing soft sediments rich in clays and organics.

  20. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism.

    Directory of Open Access Journals (Sweden)

    Mayumi Nakahara

    Full Text Available INTRODUCTION: Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM. rTM has been approved for the treatment of disseminated intravascular coagulation (DIC in Japan, and is currently undergoing a phase III clinical trial in the United States. METHODS: Histone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice. RESULTS: Histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism. CONCLUSIONS: Extracellular histones cause massive

  1. Atmospheric pressure plasma accelerates tail regeneration in tadpoles Xenopus laevis

    Science.gov (United States)

    Rivie, A.; Martus, K.; Menon, J.

    2017-08-01

    Atmospheric pressure plasma is a partially ionized gas composed of neutral and charged particles, including electrons and ions, as well as reactive oxygen species (ROS). Recently, it is utilized as possible therapy in oncology, sterilization, skin diseases, wound healing and tissue regeneration. In this study we focused on effect of plasma exposure on tail regeneration of tadpoles, Xenopus leavis with special emphasis on role of ROS, antioxidant defenses and morphological features of the regenerate. When amputated region of the tail was exposed to the helium plasma it resulted in a faster rate of growth, elevated ROS and increase in antioxidant enzymes in the regenerate compared to that of untreated control. An increase in nitric oxide (free radical) as well as activity of nitric oxide synthase(s) were observed once the cells of the regeneration blastema - a mass of proliferating cells are ready for differentiation. Microscopically the cells of the regenerate of plasma treated tadpoles show altered morphology and characteristics of cellular hypoxia and oxidative stress. We summarize that plasma exposure accelerates the dynamics of wound healing and tail regeneration through its effects on cell proliferation and differentiation as well as angiogenesis mediated through ROS signaling.

  2. Human OGG1 activity in nucleosomes is facilitated by transient unwrapping of DNA and is influenced by the local histone environment.

    Science.gov (United States)

    Bilotti, Katharina; Kennedy, Erin E; Li, Chuxuan; Delaney, Sarah

    2017-11-01

    If unrepaired, damage to genomic DNA can cause mutations and/or be cytotoxic. Single base lesions are repaired via the base excision repair (BER) pathway. The first step in BER is the recognition and removal of the nucleobase lesion by a glycosylase enzyme. For example, human oxoguanine glycosylase 1 (hOGG1) is responsible for removal of the prototypic oxidatively damaged nucleobase, 8-oxo-7,8-dihydroguanine (8-oxoG). To date, most studies of glycosylases have used free duplex DNA substrates. However, cellular DNA is packaged as repeating nucleosome units, with 145 base pair segments of DNA wrapped around histone protein octamers. Previous studies revealed inhibition of hOGG1 at the nucleosome dyad axis and in the absence of chromatin remodelers. In this study, we reveal that even in the absence of chromatin remodelers or external cofactors, hOGG1 can initiate BER at positions off the dyad axis and that this activity is facilitated by spontaneous and transient unwrapping of DNA from the histones. Additionally, we find that solution accessibility as determined by hydroxyl radical footprinting is not fully predictive of glycosylase activity and that histone tails can suppress hOGG1 activity. We therefore suggest that local nuances in the nucleosome environment and histone-DNA interactions can impact glycosylase activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Making the long tail work

    DEFF Research Database (Denmark)

    Thuesen, Christian Langhoff; Jensen, Jens Stissing; Gottlieb, Stefan Christoffer

    2009-01-01

    and Thomas 1928: 572) - a fundamental sociological principle. The Pareto principle is applied using the concept “The long tail” (Anderson 2006). Based on “the long tail” the three different production paradigms of mass production, mass customisation, and individual customisation are identified. The paper...... how attempts to develop new construction practices like partnering and lean implicitly reproduce this myth. The result is that construction research the past 25 years has been constructing the long tail in a way that hinders radical development of the construction industry. The paper concludes...

  4. Global histone modification of histone H3 in colorectal cancer and its precursor lesions.

    Science.gov (United States)

    Nakazawa, Tadao; Kondo, Tetsuo; Ma, Defu; Niu, Dongfeng; Mochizuki, Kunio; Kawasaki, Tomonori; Yamane, Tetsu; Iino, Hiroshi; Fujii, Hideki; Katoh, Ryohei

    2012-06-01

    Chromatin remodeling through histone modification is an important mechanism of epigenetic gene dysregulation in human cancers. However, little is known about global alteration of histone status during tumorigenesis and cancer progression. Histone H3 status was examined in benign and malignant colorectal tumors by immunohistochemistry and Western blotting. For immunohistochemical evaluation, 4 anti-histone H3 antibodies, specific to dimethylation at lysine 4 (H3K4me2), acetylation at lysine 9 (H3K9ac), dimethylation at lysine 9 (H3K9me2), and trimethylation at lysine 27 (H3K27me3), were used. On immunohistochemistry, H3K4me2, H3K9ac, and H3K27me3 showed no significant changes between normal and colorectal tumors. On the other hand, the global level of H3K9me2 was distinctly higher in neoplastic cells (adenoma and adenocarcinoma) than in normal glandular cells. In addition, it was significantly higher in adenocarcinoma than in adenoma. Correspondingly, Western blotting confirmed that H3K9me2 expression was significantly higher in adenocarcinomas than in normal colorectal mucosa. No alteration of H3K9me2 was observed with tumor differentiation and with the histological subtypes of colorectal cancers. These results suggest that aberration of the global H3K9me2 level is an important epigenetic event in colorectal tumorigenesis and carcinogenesis involved with gene regulation in neoplastic cells through chromatin remodeling. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Targeting histone modifications--epigenetics in cancer.

    Science.gov (United States)

    Waldmann, Tanja; Schneider, Robert

    2013-04-01

    Cancer is one of the most common human diseases. It is long known that mutations in key regulator genes are hallmarks of all cancer types. Apart from these classical genetic pathways there is more and more evidence that also epigenetic alterations are crucially involved in tumourigenesis. In this review we discuss and summarise recent findings of mechanisms responsible for cancer formation apart from the classic genetic mutations. Furthermore, we show how epigenetic and genetic mechanisms could depend on each other and contribute together to cancer formation. We focus mainly on post-translational histone modifications since they are one of the major epigenetic mechanisms regulating gene expression and when they are imbalanced this can result in cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Centromere domain organization and histone modifications

    Directory of Open Access Journals (Sweden)

    P. Bjerling

    2002-05-01

    Full Text Available Centromere function requires the proper coordination of several subfunctions, such as kinetochore assembly, sister chromatid cohesion, binding of kinetochore microtubules, orientation of sister kinetochores to opposite spindle poles, and their movement towards the spindle poles. Centromere structure appears to be organized in different, separable domains in order to accomplish these functions. Despite the conserved nature of centromere functions, the molecular genetic definition of the DNA sequences that form a centromere in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, in the fruit fly Drosophila melanogaster, and in humans has revealed little conservation at the level of centromere DNA sequences. Also at the protein level few centromere proteins are conserved in all of these four organisms and many are unique to the different organisms. The recent analysis of the centromere structure in the yeast S. pombe by electron microscopy and detailed immunofluorescence microscopy of Drosophila centromeres have brought to light striking similarities at the overall structural level between these centromeres and the human centromere. The structural organization of the centromere is generally multilayered with a heterochromatin domain and a central core/inner plate region, which harbors the outer plate structures of the kinetochore. It is becoming increasingly clear that the key factors for assembly and function of the centromere structure are the specialized histones and modified histones which are present in the centromeric heterochromatin and in the chromatin of the central core. Thus, despite the differences in the DNA sequences and the proteins that define a centromere, there is an overall structural similarity between centromeres in evolutionarily diverse eukaryotes.

  7. Histone deacetylase 8 in neuroblastoma tumorigenesis.

    Science.gov (United States)

    Oehme, Ina; Deubzer, Hedwig E; Wegener, Dennis; Pickert, Diana; Linke, Jan-Peter; Hero, Barbara; Kopp-Schneider, Annette; Westermann, Frank; Ulrich, Scott M; von Deimling, Andreas; Fischer, Matthias; Witt, Olaf

    2009-01-01

    The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis. We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally evaluated in cell culture models. Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment. Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a specific drug target for the differentiation therapy of neuroblastoma.

  8. Transport and deposition of thickened uranium tailings

    Energy Technology Data Exchange (ETDEWEB)

    Paulsen, E., E-mail: eric.paulsen@areva.ca [AREVA Resources Canada, Inc., Saskatoon, SK (Canada)

    2010-07-01

    The McClean Lake operation has experienced several problems relating to the thickened tailings disposal system. These include issues relating to segregation, inadequate pumping capacity, and unstable pipeline operation. Segregation in the tailings management facility is of particular importance since it negatively impacts the long-term containment of arsenic and the consolidation of the tails solids. These issues have direct implications on the regulatory requirements of the operation. As a result several initiatives relating to tailings thickening, transport, and deposition were proposed and implemented. This paper presents an audit of the existing tailings transport system based on the rheological requirements of homogeneous tailings as well as the proposed changes and preliminary results of this study. (author)

  9. Histone variants of the insect Plodia interpunctella during metamorphosis.

    Science.gov (United States)

    Pataryas, T A; Sekeri-Pataryas, K T; Bonner, W M; Marinou, V A

    1984-01-01

    The pattern of histone variants from the meal moth Plodia interpunctella was compared to the mouse histone variant pattern. Plodia contains histones which comigrate on two dimensional gels with H3.2, H3.3, H4 and H2A.Z in mouse. Plodia H2A.1 and H2B.1 migrate somewhat differently from the respective mouse histones. Comparison of the iodinated tryptic peptides of H2A.1 and H2A.Z from mouse and Plodia showed that the H2A.Z proteins have two iodinated peptides that comigrate in the two species and three more that are different. The H2A.1 proteins in the two species have one iodinated peptide which comigrates and two more which migrate very close to each other. The histone variants from three developmental stages, larval, pupal and adult of Plodia interpunctella were also identified and compared. The same histone variant pattern is found through all stages of development. It is concluded that histone gene expression does not change during metamorphosis in Plodia .

  10. Interpreting the language of histone and DNA modifications.

    Science.gov (United States)

    Rothbart, Scott B; Strahl, Brian D

    2014-08-01

    A major mechanism regulating the accessibility and function of eukaryotic genomes are the covalent modifications to DNA and histone proteins that dependably package our genetic information inside the nucleus of every cell. Formally postulated over a decade ago, it is becoming increasingly clear that post-translational modifications (PTMs) on histones act singly and in combination to form a language or 'code' that is read by specialized proteins to facilitate downstream functions in chromatin. Underappreciated at the time was the level of complexity harbored both within histone PTMs and their combinations, as well as within the proteins that read and interpret the language. In addition to histone PTMs, newly-identified DNA modifications that can recruit specific effector proteins have raised further awareness that histone PTMs operate within a broader language of epigenetic modifications to orchestrate the dynamic functions associated with chromatin. Here, we highlight key recent advances in our understanding of the epigenetic language encompassing histone and DNA modifications and foreshadow challenges that lie ahead as we continue our quest to decipher the fundamental mechanisms of chromatin regulation. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Histone propionylation is a mark of active chromatin.

    Science.gov (United States)

    Kebede, Adam F; Nieborak, Anna; Shahidian, Lara Zorro; Le Gras, Stephanie; Richter, Florian; Gómez, Diana Aguilar; Baltissen, Marijke P; Meszaros, Gergo; Magliarelli, Helena de Fatima; Taudt, Aaron; Margueron, Raphael; Colomé-Tatché, Maria; Ricci, Romeo; Daujat, Sylvain; Vermeulen, Michiel; Mittler, Gerhard; Schneider, Robert

    2017-12-01

    Histones are highly covalently modified, but the functions of many of these modifications remain unknown. In particular, it is unclear how histone marks are coupled to cellular metabolism and how this coupling affects chromatin architecture. We identified histone H3 Lys14 (H3K14) as a site of propionylation and butyrylation in vivo and carried out the first systematic characterization of histone propionylation. We found that H3K14pr and H3K14bu are deposited by histone acetyltransferases, are preferentially enriched at promoters of active genes and are recognized by acylation-state-specific reader proteins. In agreement with these findings, propionyl-CoA was able to stimulate transcription in an in vitro transcription system. Notably, genome-wide H3 acylation profiles were redefined following changes to the metabolic state, and deletion of the metabolic enzyme propionyl-CoA carboxylase altered global histone propionylation levels. We propose that histone propionylation, acetylation and butyrylation may act in combination to promote high transcriptional output and to couple cellular metabolism with chromatin structure and function.

  12. Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Yonggang Wang

    2014-01-01

    Full Text Available Cardiovascular disease (CVD remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs and deacetylases (HDACs are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.

  13. Germline-specific H1 variants: the "sexy" linker histones.

    Science.gov (United States)

    Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

    2016-03-01

    The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.

  14. PTEN Interacts with Histone H1 and Controls Chromatin Condensation

    Science.gov (United States)

    Chen, Zhu Hong; Zhu, Minglu; Yang, Jingyi; Liang, Hui; He, Jinxue; He, Shiming; Wang, Pan; Kang, Xi; McNutt, Michael A.; Yin, Yuxin; Shen, Wen H.

    2014-01-01

    SUMMARY Chromatin organization and dynamics are integral to global gene transcription. Histone modification influences chromatin status and gene expression. PTEN plays multiple roles in tumor suppression, development and metabolism. Here we report on the interplay of PTEN, histone H1 and chromatin. We show that loss of PTEN leads to dissociation of histone H1 from chromatin and decondensation of chromatin. PTEN deletion also results in elevation of histone H4 acetylation at lysine 16, an epigenetic marker for chromatin activation. We found that PTEN and histone H1 physically interact through their C-terminal domains. Disruption of the PTEN C-terminus promotes the chromatin association of MOF acetyltransferase and induces H4K16 acetylation. Hyperacetylation of H4K16 impairs the association of PTEN with histone H1, which constitutes regulatory feedback that may deteriorate chromatin stability. Our results demonstrate that PTEN controls chromatin condensation, thus influencing gene expression. We propose that PTEN regulates global gene transcription profiling through histones and chromatin remodeling. PMID:25199838

  15. Impact of ozonation on particle aggregation in mature fine tailings.

    Science.gov (United States)

    Liang, Jiaming; Tumpa, Fahmida; Pérez Estrada, Leonidas; Gamal El-Din, Mohamed; Liu, Yang

    2014-12-15

    The extraction of bitumen from the oil sands in Canada generates tonnes of mature fine tailings (MFT), consisting of a mineral matrix of sand, clay, and water, which without treatment requires thousands of years to fully consolidate. We assessed the performance of a novel ozonation method designed to enhance the settling of MFT and explored the mechanisms involved. The solid content of MFT obtained from oil sands tailings was adjusted to 1, 3, 5 wt % with water before applying 15, 30, and 60 min of ozonation. MFT settled after a short (15 min) ozonation treatment, resulting in a sample with clear released water on the top and condensed sludge at the bottom. The water chemistry characteristics, particles' surface charge and chemical bonding were measured. Ozonation led to the increased organic acids concentrations in MFT suspension through converting of organic matter from high to low molecular weight, and detaching organic coating on MFT particles. The pH and the concentrations of ions in the MFT suspension were changed significantly, an association of metal ions with MFT particles was promoted, and the surface charges of MFT particles were neutralized. Consequently, the MFT suspension was destabilized and MFT particle precipitation was observed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Active tails enhance arboreal acrobatics in geckos.

    Science.gov (United States)

    Jusufi, Ardian; Goldman, Daniel I; Revzen, Shai; Full, Robert J

    2008-03-18

    Geckos are nature's elite climbers. Their remarkable climbing feats have been attributed to specialized feet with hairy toes that uncurl and peel in milliseconds. Here, we report that the secret to the gecko's arboreal acrobatics includes an active tail. We examine the tail's role during rapid climbing, aerial descent, and gliding. We show that a gecko's tail functions as an emergency fifth leg to prevent falling during rapid climbing. A response initiated by slipping causes the tail tip to push against the vertical surface, thereby preventing pitch-back of the head and upper body. When pitch-back cannot be prevented, geckos avoid falling by placing their tail in a posture similar to a bicycle's kickstand. Should a gecko fall with its back to the ground, a swing of its tail induces the most rapid, zero-angular momentum air-righting response yet measured. Once righted to a sprawled gliding posture, circular tail movements control yaw and pitch as the gecko descends. Our results suggest that large, active tails can function as effective control appendages. These results have provided biological inspiration for the design of an active tail on a climbing robot, and we anticipate their use in small, unmanned gliding vehicles and multisegment spacecraft.

  17. The histone chaperone complex HIR maintains nucleosome occupancy and counterbalances impaired histone deposition in CAF-1 complex mutants.

    Science.gov (United States)

    Duc, Céline; Benoit, Matthias; Le Goff, Samuel; Simon, Lauriane; Poulet, Axel; Cotterell, Sylviane; Tatout, Christophe; Probst, Aline V

    2015-03-01

    Chromatin organization is essential for coordinated gene expression, genome stability, and inheritance of epigenetic information. The main components involved in chromatin assembly are specific complexes such as Chromatin Assembly Factor 1 (CAF-1) and Histone Regulator (HIR), which deposit histones in a DNA synthesis-dependent or -independent manner, respectively. Here, we characterize the role of the plant orthologs Histone Regulator A (HIRA), Ubinuclein (UBN) and Calcineurin Binding protein 1 (CABIN1), which constitute the HIR complex. Arabidopsis loss-of-function mutants for the various subunits of the complex are viable, but hira mutants show reduced fertility. We show that loss of HIRA reduces extractable histone H3 protein levels and decreases nucleosome occupancy at both actively transcribed genes and heterochromatic regions. Concomitantly, HIRA contributes to maintenance of silencing of pericentromeric repeats and certain transposons. A genetic analysis based on crosses between mutants deficient in subunits of the CAF-1 and HIR complexes showed that simultaneous loss of both the CAF-1 and HIR histone H3 chaperone complexes severely affects plant survival, growth and reproductive development. Our results suggest that HIRA partially rescues impaired histone deposition in fas mutants to preserve nucleosome occupancy, implying plasticity in histone variant interaction and deposition. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  18. Hypoacetylation, hypomethylation, and dephosphorylation of H2B histones and excessive histone deacetylase activity in DU-145 prostate cancer cells.

    Science.gov (United States)

    Cang, Shundong; Xu, Xiaobin; Ma, Yuehua; Liu, Delong; Chiao, J W

    2016-01-12

    Hypoacetylation on histone H3 of human prostate cancer cells has been described. Little is known about the modifications of other histones from prostate cancer cells. Histones were isolated from the prostate cancer cell line DU-145 and the non-malignant prostatic cell line RC170N/h. Post-translational modifications of histone H2B were determined by liquid chromatography-mass spectrometry (LC-MS)/MS. The histone H2B of the prostate cancer cell line DU-145 was found to have hypoacetylation, hypomethylation, and dephosphorylation as compared to the non-malignant prostatic cell line RC170N/h. H2B regained acetylation on multiple lysine residues, phosphorylation on Thr19, and methylation on Lys23 and Lys43 in the DU-145 cells after sodium butyrate treatment. The histone H2B of DU-145 prostate cancer cells are hypoacetylated, hypomethylated, and dephosphorylated. Histone deacetylase inhibitor reversed this phenotype. Epigenetic agent may therefore be useful for prostate cancer therapy and worth further investigation.

  19. Hypoacetylation, hypomethylation, and dephosphorylation of H2B histones and excessive histone deacetylase activity in DU-145 prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Shundong Cang

    2016-01-01

    Full Text Available Abstract Background Hypoacetylation on histone H3 of human prostate cancer cells has been described. Little is known about the modifications of other histones from prostate cancer cells. Methods Histones were isolated from the prostate cancer cell line DU-145 and the non-malignant prostatic cell line RC170N/h. Post-translational modifications of histone H2B were determined by liquid chromatography-mass spectrometry (LC-MS/MS. Results The histone H2B of the prostate cancer cell line DU-145 was found to have hypoacetylation, hypomethylation, and dephosphorylation as compared to the non-malignant prostatic cell line RC170N/h. H2B regained acetylation on multiple lysine residues, phosphorylation on Thr19, and methylation on Lys23 and Lys43 in the DU-145 cells after sodium butyrate treatment. Conclusions The histone H2B of DU-145 prostate cancer cells are hypoacetylated, hypomethylated, and dephosphorylated. Histone deacetylase inhibitor reversed this phenotype. Epigenetic agent may therefore be useful for prostate cancer therapy and worth further investigation.

  20. A Tale of Two Tails: Exploring Stellar Populations in the Tidal Tails of NGC 3256

    Science.gov (United States)

    Rodruck, Michael; Charlton, Jane C.; Konstantopoulos, Iraklis

    2016-01-01

    Galaxy interactions can inject material into the intergalactic medium via violent gravitational dynamics, often visualized in tidal tails. The composition of these tails has remained a mystery, as previous studies have focused on detecting tidal features, rather than the composite material itself. We have developed an observing program using deep, multiband imaging to probe the chaotic regions of tidal tails in search for an underlying stellar population. NGC 3256's twin tidal tails serve as a case study for this new technique. Our results show color values of u - g = 1.15 and r - i = 0.08 for the Western tail, and u - g = 1.33 and r - i = 0.22 for the Eastern tail, corresponding to discrepant ages between the tails of approximately 320 Myr and 785 Myr, respectively. With the interaction age of the system measured at 400 Myr, we find the stellar light in Western tail to be dominated by disrupted star clusters formed during and after the interaction, whereas the light from the Eastern tail is dominated by a 10 Gyr population originating from the host galaxies. We fit the Eastern tail color to a Mixed Stellar Population (MSP) model comprised 94% by mass of a 10 Gyr stellar population, and 6% of a 309 Myr population. We find 52% of the bolometric flux originating from this 10 Gyr population. We also detect a blue to red color gradient in each tail, running from galactic center to tail tip. In addition to tidal tail light, we detect 29 star cluster candidates (SCCs) in the Western tail and 19 in the Eastern, with mean ages of 282 Myr and 98 Myr respectively. Interestingly, we find an excess of very blue SCCs in the Eastern tail as compared to the Western tail, marking a recent, small episode of star formation.

  1. Microbially-accelerated consolidation of oil sands tailings. Pathway II: solid phase biogeochemistry

    Directory of Open Access Journals (Sweden)

    Tariq eSiddique

    2014-03-01

    Full Text Available Consolidation of clay particles in aqueous tailings suspensions is a major obstacle to effective management of oil sands tailings ponds in northern Alberta, Canada. We have observed that microorganisms indigenous to the tailings ponds accelerate consolidation of mature fine tailings (MFT during active metabolism by using two biogeochemical pathways. In Pathway I, microbes alter porewater chemistry to indirectly increase consolidation of MFT. Here, we describe Pathway II comprising significant, direct and complementary biogeochemical reactions with MFT mineral surfaces. An anaerobic microbial community comprising Bacteria (predominantly Clostridiales, Synergistaceae and Desulfobulbaceae and Archaea (Methanolinea/Methanoregula and Methanosaeta transformed FeIII minerals in MFT to amorphous FeII minerals during methanogenic metabolism of an added organic substrate. Synchrotron analyses suggested that ferrihydrite (5Fe2O3. 9H2O and goethite (α-FeOOH were the dominant FeIII minerals in MFT. The formation of amorphous iron sulfide (FeS and possibly green rust entrapped and masked electronegative clay surfaces in amended MFT. Both Pathways I and II reduced the surface charge potential (repulsive forces of the clay particles in MFT, which aided aggregation of clays and formation of networks of pores, as visualized using cryo-scanning electron microscopy. These reactions facilitated the egress of porewater from MFT and increased consolidation of tailings solids. These results have large-scale implications for management and reclamation of oil sands tailings ponds, a burgeoning environmental issue for the public and government regulators.

  2. Performance Comparison between Neutralization Tailings and Flotation Tailings Used for Backfill Mix and Mechanism Analysis

    Directory of Open Access Journals (Sweden)

    Bin Han

    2016-01-01

    Full Text Available A comparison test of different tailings used for underground backfill was conducted, using neutralized tailings from BIOX and flotation tailings of Jinfeng Mine. Laboratory comparison test results show that, with neutralized tailings, when the cement dosage is at 19%, backfill UCS after 7 days, 14 days, and 28 days are 105%–163%, 80%–102%, and 33%–43%, respectively, which are higher than those of flotation tailings. When the cement dosage is at 12%, backfill UCS after 7 days, 14 days, and 28 days are 58%–77%, 50%–60%, and 28%–51%, respectively, which are higher than those of flotation tailings. Slurry fluidity of neutralized tailings is lower than that of flotation tailings, while, in these two tailings, the difference of slump and diffusivity values is less than 6%, which is not a significant difference in slurry fluidity. The reason for neutralized tailings showing higher UCS is as follows: during backfill curing, neutralization tailings produce abundant crystals of CaSO4·2H2O in interlaced structure which helps in combining aggregates closely; CaSO4·2H2O hydrates with C3A C4AF contained in the cement and forms clavate cement bacillus which works as a micro reinforcing steel bar. The test proved that neutralized tailings are more optimal for backfilling.

  3. Mapping and Quantifying Surface Charges on Clay Nanoparticles.

    Science.gov (United States)

    Liu, Jun; Gaikwad, Ravi; Hande, Aharnish; Das, Siddhartha; Thundat, Thomas

    2015-09-29

    Understanding the electrical properties of clay nanoparticles is very important since they play a crucial role in every aspect of oil sands processing, from bitumen extraction to sedimentation in mature fine tailings (MFT). Here, we report the direct mapping and quantification of surface charges on clay nanoparticles using Kelvin probe force microscopy (KPFM) and electrostatic force microscopy (EFM). The morphology of clean kaolinite clay nanoparticles shows a layered structure, while the corresponding surface potential map shows a layer-dependent charge distribution. More importantly, a surface charge density of 25 nC/cm(2) was estimated for clean kaolinite layers by using EFM measurements. On the other hand, the EFM measurements show that the clay particles obtained from the tailings demonstrate a reduced surface charge density of 7 nC/cm(2), which may be possibly attributed to the presence of various bituminous compounds residing on the clay surfaces.

  4. Characterization and dewatering of flotation technological tailings

    Directory of Open Access Journals (Sweden)

    Grigorova I.

    2014-01-01

    Full Text Available The treatment of flotation tailings is today a subject of interest in mineral processing because of the potential of wasted materials as an actual mineral resource and because of environmental reasons. Decantation ponds are found at almost every mine in the world. They are large earth fill dams containing the residue of the milling process to extract metals from mined ores. Traditional wet tailings disposal has been problematic due to the risk of ground water contamination and the difficulty in rehabilitating storage sites. Tailings dams are at risk of failure due to leakage, instability, liquefaction, and poor design. In the last few years the use of paste technology in the disposal of mine tailings is increasingly studied as an option to conventional tailings dams. The Lucky Invest Concentrator is located in the Eastern Rhodopes Mountain of Bulgaria. Since 1959 lead-zinc ores are dressed. Finally, during the flotation cycle lead and zinc concentrates are produced. The final technological processing waste precipitates in tailing pond. Research and development program has started to established opportunities to obtain dry deposit of the ore processing residue and analyses the feature of new tailing disposal method. The tailings particle size distributions and chemical compositions were determined. The data from laboratory and pilot scale tests clearly illustrate that there are the possibilities to obtaine lead-zinc dewatered tailings. The experimental results show that new cyclone modifications have a potential in dewatering technology of flotation tailings. It appears that dewatering cyclones can be an approach on new tailings pond elimination technology.

  5. Mobilization and transport of metal-rich colloidal particles from mine tailings into soil under transient chemical and physical conditions.

    Science.gov (United States)

    Lu, Cong; Wu, Yaoguo; Hu, Sihai; Raza, Muhammad Ali; Fu, Yilin

    2016-04-01

    Exposed mine tailing wastes with considerable heavy metals can release hazardous colloidal particles into soil under transient chemical and physical conditions. Two-layered packed columns with tailings above and soils below were established to investigate mobilization and transport of colloidal particles from metal-rich mine tailings into soil under transient infiltration ionic strength (IS: 100, 20, 2 mM) and flow rate (FR: 20.7, 41, and 62.3 mm h(-1)), with Cu and Pb as representatives of the heavy metals. Results show that the tailing particles within the colloidal size (below 2 μm) were released from the columns. A step-decrease in infiltration IS and FR enhanced, whereas a step-increase in the IS and FR restrained the release of tailing particles from the column. The effects of step-changing FR were unexpected due to the small size of the released tailing particles (220-342 nm, being not sensitive to hydrodynamic shear force), the diffusion-controlled particle release process and the relatively compact pore structure. The tailing particles present in the solution with tested IS were found negatively charged and more stable than soil particles, which provides favorable conditions for tailing particles to be transported over a long distance in the soil. The mobilization and transport of Cu and Pb from the tailings into soil were mediated by the tailing particles. Therefore, the inherent toxic tailing particles could be considerably introduced into soil under certain conditions (IS reduction or FR decrease), which may result in serious environmental pollution.

  6. Chromatin Dynamics during Nucleotide Excision Repair: Histones on the Move

    Directory of Open Access Journals (Sweden)

    Sophie E. Polo

    2012-09-01

    Full Text Available It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well-characterized Nucleotide Excision Repair (NER pathway. We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity. In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair.

  7. Can changes in histone acetylation contribute to memory formation?

    Science.gov (United States)

    Lopez-Atalaya, Jose P; Barco, Angel

    2014-12-01

    Neuronal histone acetylation has been postulated to be a mnemonic substrate and a target for memory enhancers and neuropsychiatric drugs. Here we critically evaluate this view and examine the apparent conflict between the proposed instructive role for histone acetylation in memory-related transcription and the insights derived from genomic and genetic studies in other systems. We next discuss the suitability of activity-dependent neuronal histone acetylation as a mnemonic substrate and debate alternative interpretations of current evidence. We believe that further progress in our understanding of the role of histone acetylation and other epigenetic modifications in neuronal plasticity, memory, and neuropsychiatric disorders requires a clear discrimination between cause and effect so that novel epigenetics-related processes can be distinguished from classical transcriptional mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. New histone supply regulates replication fork speed and PCNA unloading

    DEFF Research Database (Denmark)

    Mejlvang, Jakob; Feng, Yunpeng; Alabert, Constance

    2014-01-01

    Correct duplication of DNA sequence and its organization into chromatin is central to genome function and stability. However, it remains unclear how cells coordinate DNA synthesis with provision of new histones for chromatin assembly to ensure chromosomal stability. In this paper, we show...... that replication fork speed is dependent on new histone supply and efficient nucleosome assembly. Inhibition of canonical histone biosynthesis impaired replication fork progression and reduced nucleosome occupancy on newly synthesized DNA. Replication forks initially remained stable without activation...... unloading is delayed in the absence of nucleosome assembly. We propose that coupling of fork speed and PCNA unloading to nucleosome assembly provides a simple mechanism to adjust DNA replication and maintain chromatin integrity during transient histone shortage....

  9. Breaking the histone code with quantitative mass spectrometry.

    Science.gov (United States)

    Britton, Laura-Mae P; Gonzales-Cope, Michelle; Zee, Barry M; Garcia, Benjamin A

    2011-10-01

    Histone post-translational modifications (PTMs) comprise one of the most intricate nuclear signaling networks that govern gene expression in a long-term and dynamic fashion. These PTMs are considered to be 'epigenetic' or heritable from one cell generation to the next and help establish genomic expression patterns. While much of the analyses of histones have historically been performed using site-specific antibodies, these methods are replete with technical obstacles (i.e., cross-reactivity and epitope occlusion). Mass spectrometry-based proteomics has begun to play a significant role in the interrogation of histone PTMs, revealing many new aspects of these modifications that cannot be easily determined with standard biological approaches. Here, we review the accomplishments of mass spectrometry in the histone field, and outline the future roadblocks that must be overcome for mass spectrometry-based proteomics to become the method of choice for chromatin biologists.

  10. High-resolution genome-wide mapping of histone modifications.

    Science.gov (United States)

    Roh, Tae-young; Ngau, Wing Chi; Cui, Kairong; Landsman, David; Zhao, Keji

    2004-08-01

    The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules. Post-translational histone modifications play an essential role in modifying chromatin structure. Here we apply a combination of SAGE and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5' end of a gene's coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5' end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes.

  11. Chromatin Dynamics during Nucleotide Excision Repair: Histones on the Move

    Science.gov (United States)

    Adam, Salomé; Polo, Sophie E.

    2012-01-01

    It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well-characterized Nucleotide Excision Repair (NER) pathway. We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity. In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair. PMID:23109890

  12. Profitable tail-end production

    Energy Technology Data Exchange (ETDEWEB)

    Pinchbeck, R.H.

    1997-12-31

    This presentation discusses the origins of the present challenge faced in making mature oil fields profitable in the North Sea. It briefly examines the origins of these challenges, which are rooted in the industrial psychology of the North Sea. It develops a methodological formula for the successful re-engineering of inefficiently-run assets, focusing in particular on the personnel management aspects. It identifies some key areas to seek sustainable cost reductions and recognises the importance of renewing the context for investment in tail-end fields. Finally, it speculates about the way in which the learnings developed in the experiences of the last few years will influence the future of the North Sea. 2 refs.

  13. Spacecraft sails through comet's tail

    Science.gov (United States)

    Katzoff, Judith A.

    Comet Giacobini-Zinner may not have a conventional bow shock, but the “interaction region” where the comet's sheath collides with the solar wind is a far more turbulent plasma than had been anticipated. On September 13, 2 days after the International Cometary Explorer (ICE) became the first spacecraft ever to pass through a comet's tail (Eos, September 3, 1985, p. 625), mission scientists gathered at the National Aeronautics and Space Administration's Goddard Space Flight Center (GSFC) to review their preliminary results. One scientist attending the news conference said he understood the interaction region to be “the most turbulent region that we have seen in the solar system to date.”

  14. Specific distribution of the Saccharomyces cerevisiae linker histone homolog HHO1p in the chromatin

    OpenAIRE

    Freidkin, Ilya; Katcoff, Don J.

    2001-01-01

    In virtually all eukaryotic organisms, linker DNA between nucleosomes is associated with a histone termed linker histone or histone H1. In Saccharomyces cerevisiae, HHO1 encodes a putative linker histone with very significant homology to histone H1. The encoded protein is expressed in the nucleus, but has not been shown to affect global chromatin structure, nor has its deletion shown any detectable phenotype. In vitro chromatin assembly experiments with recombinant HHO1p have shown that it is...

  15. Histone H3.3 Mutations: A Variant Path to Cancer

    OpenAIRE

    Yuen, Benjamin T.K.; Knoepfler, Paul S.

    2013-01-01

    A host of cancer types exhibit aberrant histone modifications. Recently, distinct and recurrent mutations in a specific histone variant, histone H3.3, have been implicated in a high proportion of malignant pediatric brain cancers. The presence of mutant H3.3 histone disrupts epigenetic post-translational modifications near genes involved in cancer processes and in brain function. Here, we propose several possible mechanisms by which mutant H3.3 histones may act to promote tumorigenesis. Furth...

  16. H2A and H2B tails are essential to properly reconstitute nucleosome core particles.

    Science.gov (United States)

    Bertin, Aurélie; Durand, Dominique; Renouard, Madalena; Livolant, Françoise; Mangenot, Stéphanie

    2007-11-01

    The conformation of recombinant Nucleosome Core Particles (NCPs) lacking H2A and H2B histone tails (gH2AgH2B) are studied. The migration of these particles in acrylamide native gels is slowed down compared to intact reconstituted NCPs. gH2AgH2B NCPs are also much more sensitive to nuclease digestion than intact NCPs. Small angle X-ray scattering (SAXS) experiments point out that the absence of H2A and H2B tails produces small but significant conformational changes of the octamers conformation (without wrapped DNA), whereas gH2AgH2B NCP conformations are significantly altered. A separation of about 25-30 bp from the core could account for the experimental curves, but other types of DNA superhelix deformation cannot be excluded. The distorted gH2AgH2B octamer may not allow the correct winding of DNA around the core. The absence of the H2A and H2B tails would further prevent the secondary sliding of the DNA around the core and therefore impedes the stabilisation of the particle. Cryo-electron microscopy on the same particles also shows a detachment of DNA portions from the particle core. The effect is even stronger because the vitrification of the samples worsens the instability of gH2AgH2B NCPs.

  17. Tailed Radio Sources in the CDFS Field

    Indian Academy of Sciences (India)

    Using 1.4 GHz ATCA & VLA images with 5.5 GHz ATCA data, we present a sample of 12 bent-tailed galaxies over the 4 deg2 area of the Chandra Deep Field South (CDFS). We find 10 new sources, one of which is possibly the highest red-shift bent-tailed galaxy detected at ∼ 2.

  18. Treatment of a diamond mine's slimes tailings

    African Journals Online (AJOL)

    2006-07-21

    Jul 21, 2006 ... ity water in the dam which is not being recycled back into the process. ... process is course tailings (≥ +1 mm) and fine tailings or slimes .... the thickener. It was expected to achieve faster settling rates using this method. A production thickener, measuring 30 m in diameter and having a total volume of 1 970 ...

  19. Anatomy of a lactococcal phage tail

    NARCIS (Netherlands)

    Mc Grath, S; Neve, H; Seegers, JFML; Eijlander, R; Vegge, CS; Brondsted, L; Heller, KJ; Fitzgerald, GF; Vogensen, FK; van Sinderen, D

    Bacteriophages of the Siphoviridae family utilize a long noncontractile tail to recognize, adsorb to, and inject DNA into their bacterial host. The tail anatomy of the archetypal Siphoviridae X has been well studied, in contrast to phages infecting gram-positive bacteria. This report outlines a

  20. A 6-alkylsalicylate histone acetyltransferase inhibitor inhibits histone acetylation and pro-inflammatory gene expression in murine precision-cut lung slices

    NARCIS (Netherlands)

    Bosch, van den Thea; Leus, Niek G J; Wapenaar, Hannah; Boichenko, Alexander; Hermans, Jos; Bischoff, Rainer; Haisma, Hidde J; Dekker, Frank J

    Lysine acetylations are post-translational modifications of cellular proteins, that are crucial in the regulation of many cellular processes. Lysine acetylations on histone proteins are part of the epigenetic code regulating gene transcription and are installed by histone acetyltransferases.

  1. A barcode screen for epigenetic regulators reveals a role for the NuB4/HAT-B histone acetyltransferase complex in histone turnover.

    Directory of Open Access Journals (Sweden)

    Kitty F Verzijlbergen

    2011-10-01

    Full Text Available Dynamic modification of histone proteins plays a key role in regulating gene expression. However, histones themselves can also be dynamic, which potentially affects the stability of histone modifications. To determine the molecular mechanisms of histone turnover, we developed a parallel screening method for epigenetic regulators by analyzing chromatin states on DNA barcodes. Histone turnover was quantified by employing a genetic pulse-chase technique called RITE, which was combined with chromatin immunoprecipitation and high-throughput sequencing. In this screen, the NuB4/HAT-B complex, containing the conserved type B histone acetyltransferase Hat1, was found to promote histone turnover. Unexpectedly, the three members of this complex could be functionally separated from each other as well as from the known interacting factor and histone chaperone Asf1. Thus, systematic and direct interrogation of chromatin structure on DNA barcodes can lead to the discovery of genes and pathways involved in chromatin modification and dynamics.

  2. Structural Mechanisms of Nucleosome Recognition by Linker Histones.

    Science.gov (United States)

    Zhou, Bing-Rui; Jiang, Jiansheng; Feng, Hanqiao; Ghirlando, Rodolfo; Xiao, T Sam; Bai, Yawen

    2015-08-20

    Linker histones bind to the nucleosome and regulate the structure of chromatin and gene expression. Despite more than three decades of effort, the structural basis of nucleosome recognition by linker histones remains elusive. Here, we report the crystal structure of the globular domain of chicken linker histone H5 in complex with the nucleosome at 3.5 Å resolution, which is validated using nuclear magnetic resonance spectroscopy. The globular domain sits on the dyad of the nucleosome and interacts with both DNA linkers. Our structure integrates results from mutation analyses and previous cross-linking and fluorescence recovery after photobleach experiments, and it helps resolve the long debate on structural mechanisms of nucleosome recognition by linker histones. The on-dyad binding mode of the H5 globular domain is different from the recently reported off-dyad binding mode of Drosophila linker histone H1. We demonstrate that linker histones with different binding modes could fold chromatin to form distinct higher-order structures. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?

    Science.gov (United States)

    Harrison, Ian F; Dexter, David T

    2013-10-01

    Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD? Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Alterations of Histone H1 Phosphorylation During Bladder Carcinogenesis

    Science.gov (United States)

    Telu, Kelly H.; Abbaoui, Besma; Thomas-Ahner, Jennifer M.; Zynger, Debra L.; Clinton, Steven K.

    2013-01-01

    There is a crucial need for development of prognostic and predictive biomarkers in human bladder carcinogenesis in order to personalize preventive and therapeutic strategies and improve outcomes. Epigenetic alterations, such as histone modifications, are implicated in the genetic dysregulation that is fundamental to carcinogenesis. Here we focus on profiling the histone modifications during the progression of bladder cancer. Histones were extracted from normal human bladder epithelial cells, an immortalized human bladder epithelial cell line (hTERT), and four human bladder cancer cell lines (RT4, J82, T24, and UMUC3) ranging from superficial low-grade to invasive high-grade cancers. Liquid Chromatography-Mass Spectrometry (LC-MS) profiling revealed a statistically significant increase in phosphorylation of H1 linker histones from normal human bladder epithelial cells to low-grade superficial to high-grade invasive bladder cancer cells. This finding was further validated by immunohistochemical staining of the normal epithelium and transitional cell cancer from human bladders. Cell cycle analysis of histone H1 phosphorylation by western blotting showed an increase of phosphorylation from G0/G1 phase to M phase, again supporting this as a proliferative marker. Changes in histone H1 phosphorylation status may further clarify epigenetic changes during bladder carcinogenesis and provide diagnostic and prognostic biomarkers or targets for future therapeutic interventions. PMID:23675690

  5. Injurious tail biting in pigs: how can it be controlled in existing systems without tail docking?

    Science.gov (United States)

    D'Eath, R B; Arnott, G; Turner, S P; Jensen, T; Lahrmann, H P; Busch, M E; Niemi, J K; Lawrence, A B; Sandøe, P

    2014-09-01

    Tail biting is a serious animal welfare and economic problem in pig production. Tail docking, which reduces but does not eliminate tail biting, remains widespread. However, in the EU tail docking may not be used routinely, and some 'alternative' forms of pig production and certain countries do not allow tail docking at all. Against this background, using a novel approach focusing on research where tail injuries were quantified, we review the measures that can be used to control tail biting in pigs without tail docking. Using this strict criterion, there was good evidence that manipulable substrates and feeder space affect damaging tail biting. Only epidemiological evidence was available for effects of temperature and season, and the effect of stocking density was unclear. Studies suggest that group size has little effect, and the effects of nutrition, disease and breed require further investigation. The review identifies a number of knowledge gaps and promising avenues for future research into prevention and mitigation. We illustrate the diversity of hypotheses concerning how different proposed risk factors might increase tail biting through their effect on each other or on the proposed underlying processes of tail biting. A quantitative comparison of the efficacy of different methods of provision of manipulable materials, and a review of current practices in countries and assurance schemes where tail docking is banned, both suggest that daily provision of small quantities of destructible, manipulable natural materials can be of considerable benefit. Further comparative research is needed into materials, such as ropes, which are compatible with slatted floors. Also, materials which double as fuel for anaerobic digesters could be utilised. As well as optimising housing and management to reduce risk, it is important to detect and treat tail biting as soon as it occurs. Early warning signs before the first bloody tails appear, such as pigs holding their tails tucked

  6. Analysis of Heavy-Tailed Time Series

    DEFF Research Database (Denmark)

    Xie, Xiaolei

    This thesis is about analysis of heavy-tailed time series. We discuss tail properties of real-world equity return series and investigate the possibility that a single tail index is shared by all return series of actively traded equities in a market. Conditions for this hypothesis to be true...... are identified. We study the eigenvalues and eigenvectors of sample covariance and sample auto-covariance matrices of multivariate heavy-tailed time series, and particularly for time series with very high dimensions. Asymptotic approximations of the eigenvalues and eigenvectors of such matrices are found...... and expressed in terms of the parameters of the dependence structure, among others. Furthermore, we study an importance sampling method for estimating rare-event probabilities of multivariate heavy-tailed time series generated by matrix recursion. We show that the proposed algorithm is efficient in the sense...

  7. Why are most EU pigs tail docked?

    DEFF Research Database (Denmark)

    D'eath, R.B.; Niemi, J.K.; Vosough Ahmadi, B.

    2016-01-01

    for Danish production (0.7 m2/pig); ‘Standard Undocked’, which is the same as ‘Standard Docked’ but with no tail docking, ‘Efficient Undocked’ and ‘Enhanced Undocked’, which have increased solid floor area (0.9 and 1.0 m2/pig, respectively) provision of loose manipulable materials (100 and 200 g/straw per...... pig per day) and no tail docking. A decision tree model based on data from Danish and Finnish pig production suggests that Standard Docked provides the highest economic gross margin with the least tail biting. Given our assumptions, Enhanced Undocked is the least economic, although Efficient Undocked...... and enforcement by Member States. Widespread use of tail docking seems to be accepted, mainly because the alternative steps that producers are required to take before resorting to it are not specified in detail. By tail docking, producers are acting in their own best interests. We suggest that for the practice...

  8. [Effect of TSA and VPA treatment on long-tailed macaque (Macaca fascicularis)-pig interspecies somatic cell nuclear transfer].

    Science.gov (United States)

    Qin, Zu-Xing; Huang, Gao-Bo; Luo, Jun; Ning, Shu-Fang; Lu, Sheng-Sheng; Lu, Ke-Huan

    2012-03-01

    Long-tailed macaque-pig interspecies somatic cell nuclear transfer (iSCNT) is beneficial to yield embryonic stem cells from iSCNT embryos with similar genetic background as human, which can be used as materials for medical and basic research. The primary objective of this study was to investigate the effects of concentrations and treatment duration of two histone deacetylase inhibitors-Trichostatin A (TSA) and Valproic acid (VPA) and two different embryo culture media (PZM-3 and HECM-10) on the in vitro development of iSCNT embryos. The results suggested that when PZM-3 was used as the embryo culture medium, the blastocyst rate of 10 nmol/L TSA treatment for 48 h was significantly higher than the control group (22.78% vs 9.86%, PTSA treatment could enhance the in vitro developmental potential of long-tailed macaque-pig iSCNT embryos.

  9. Histone deacetylase inhibitors repress chondrosarcoma cell proliferation.

    Science.gov (United States)

    Zhu, Jiaxue; Gu, Jianhua; Ma, Jie; Xu, Zhixing; Tao, Hairong

    2015-01-01

    Due to the high resistance to conventional therapy, there is still no convincingly effective treatment for chondrosarcoma. As a promising new treatment strategy, histone deacetylase inhibitors (HDACIs) have been reported to induce cell arrest, apoptosis and differentiation in some kinds of malignancies, but how HDACi exert their effects on chondrosarcoma is not well understood yet. We investigated the effects of HDACIs trichostatin A (TSA) and sodium valproate (VPA) on chondrosarcoma cells in vitro and in vivo. The cell proliferation and cell cycle were examined in two chondrosarcoma cell lines, SW1353 and JJ012, by MTS and flow cytometry assays, respectively. The in vivo effects of HDACIs were investigated by assessing the chondrosarcoma growth in a mouse xenograft model. Our results showed that TSA and VPA significantly repressed the proliferation of chondrosarcoma cells in a concentration-dependent manner. Flow cytometry indicated that TSA arrested the cell cycle in G2/M phase and VPA arrested the cell cycle in G1 phase. The tumor growth was markedly suppressed in mice treated with TSA and VPA. HDACIs significantly repress the proliferation of chondrosarcoma cells in vitro and in vivo. Our findings imply that HDACIs may provide a novel therapeutic target for the treatment of chondrosarcoma.

  10. Chromatin modification by PSC occurs at one PSC per nucleosome and does not require the acidic patch of histone H2A.

    Directory of Open Access Journals (Sweden)

    Stanley M Lo

    Full Text Available Chromatin architecture is regulated through both enzymatic and non-enzymatic activities. For example, the Polycomb Group (PcG proteins maintain developmental gene silencing using an array of chromatin-based mechanisms. The essential Drosophila PcG protein, Posterior Sex Combs (PSC, compacts chromatin and inhibits chromatin remodeling and transcription through a non-enzymatic mechanism involving nucleosome bridging. Nucleosome bridging is achieved through a combination of nucleosome binding and self-interaction. Precisely how PSC interacts with chromatin to bridge nucleosomes is not known and is the subject of this work. We determine the stoichiometry of PSC-chromatin interactions in compact chromatin (in which nucleosomes are bridged using Scanning Transmission Electron Microscopy (STEM. We find that full compaction occurs with one PSC per nucleosome. In addition to compacting chromatin, we show that PSC oligomerizes nucleosome arrays. PSC-mediated oligomerization of chromatin occurs at similar stoichiometry as compaction suggesting it may also involve nucleosome bridging. Interactions between the tail of histone H4 and the acidic patch of histone H2A are important for chromatin folding and oligomerization, and several chromatin proteins bind the histone H2A acidic patch. However, mutation of the acidic patch of histone H2A does not affect PSC's ability to inhibit chromatin remodeling or bridge nucleosomes. In fact, PSC does not require nucleosomes for bridging activity but can bridge naked DNA segments. PSC clusters nucleosomes on sparsely assembled templates, suggesting it interacts preferentially with nucleosomes over bare DNA. This may be due to the ability of PSC to bind free histones. Our data are consistent with a model in which each PSC binds a nucleosome and at least one other PSC to directly bridge nucleosomes and compact chromatin, but also suggest that naked DNA can be included in compacted structures. We discuss how our data

  11. CHARGE Association

    Directory of Open Access Journals (Sweden)

    Semanti Chakraborty

    2012-01-01

    Full Text Available We present here a case of 17-year-old boy from Kolkata presenting with obesity, bilateral gynecomastia, mental retardation, and hypogonadotrophic hypogonadism. The patient weighed 70 kg and was of 153 cm height. Facial asymmetry (unilateral facial palsy, gynecomastia, decreased pubic and axillary hair, small penis, decreased right testicular volume, non-palpable left testis, and right-sided congenital inguinal hernia was present. The patient also had disc coloboma, convergent squint, microcornea, microphthalmia, pseudohypertelorism, low set ears, short neck, and choanalatresia. He had h/o VSD repaired with patch. Laboratory examination revealed haemoglobin 9.9 mg/dl, urea 24 mg/dl, creatinine 0.68 mg/dl. IGF1 77.80 ng/ml (decreased for age, GH <0.05 ng/ml, testosterone 0.25 ng/ml, FSH-0.95 ΅IU/ml, LH 0.60 ΅IU/ml. ACTH, 8:00 A.M cortisol, FT3, FT4, TSH, estradiol, DHEA-S, lipid profile, and LFT was within normal limits. Prolactin was elevated at 38.50 ng/ml. The patient′s karyotype was 46XY. Echocardiography revealed ventricularseptal defect closed with patch, grade 1 aortic regurgitation, and ejection fraction 67%. Ultrasound testis showed small right testis within scrotal sac and undescended left testis within left inguinal canal. CT scan paranasal sinuses revealed choanalatresia and deviation of nasal septum to the right. Sonomammography revealed bilateral proliferation of fibroglandular elements predominantly in subareoalar region of breasts. MRI of brain and pituitary region revealed markedly atrophic pituitary gland parenchyma with preserved infundibulum and hypothalamus and widened suprasellar cistern. The CHARGE association is an increasingly recognized non-random pattern of congenital anomalies comprising of coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities, and/or deafness. [1] These anomalies have a higher probability of occurring together. In this report, we have

  12. SUMOylated ORC2 Recruits a Histone Demethylase to Regulate Centromeric Histone Modification and Genomic Stability

    Directory of Open Access Journals (Sweden)

    Chao Huang

    2016-04-01

    Full Text Available Origin recognition complex 2 (ORC2, a subunit of the ORC, is essential for DNA replication initiation in eukaryotic cells. In addition to a role in DNA replication initiation at the G1/S phase, ORC2 has been shown to localize to the centromere during the G2/M phase. Here, we show that ORC2 is modified by small ubiquitin-like modifier 2 (SUMO2, but not SUMO1, at the G2/M phase of the cell cycle. SUMO2-modification of ORC2 is important for the recruitment of KDM5A in order to convert H3K4me3 to H3K4me2, a “permissive” histone marker for α-satellite transcription at the centromere. Persistent expression of SUMO-less ORC2 led to reduced α-satellite transcription and impaired pericentric heterochromatin silencing, which resulted in re-replication of heterochromatin DNA. DNA re-replication eventually activated the DNA damage response, causing the bypass of mitosis and the formation of polyploid cells. Thus, ORC2 sustains genomic stability by recruiting KDM5A to maintain centromere histone methylation in order to prevent DNA re-replication.

  13. Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory

    Science.gov (United States)

    Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

    2011-01-01

    Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

  14. The evolution of tail weaponization in amniotes.

    Science.gov (United States)

    Arbour, Victoria M; Zanno, Lindsay E

    2018-01-31

    Weaponry, for the purpose of intraspecific combat or predator defence, is one of the most widespread animal adaptations, yet the selective pressures and constraints governing its phenotypic diversity and skeletal regionalization are not well understood. Here, we investigate the evolution of tail weaponry in amniotes, a rare form of weaponry that nonetheless evolved independently among a broad spectrum of life including mammals, turtles and dinosaurs. Using phylogenetic comparative methods, we test for links between morphology, ecology and behaviour in extant amniotes known to use the tail as a weapon, and in extinct taxa bearing osseous tail armaments. We find robust ecological and morphological correlates of both tail lashing behaviour and bony tail weaponry, including large body size, body armour and herbivory, suggesting these life-history parameters factor into the evolution of antipredator behaviours and tail armaments. We suggest that the evolution of tail weaponry is rare because large, armoured herbivores are uncommon in extant terrestrial faunas, as they have been throughout evolutionary history. © 2018 The Author(s).

  15. APPLICATION OF POSTFLOTATION TAILINGS IN HYDROENGINEERING STRUCTURES

    Directory of Open Access Journals (Sweden)

    Katarzyna Stefaniak

    2017-01-01

    Full Text Available Economic development stimulated by the increased demand for production of consumer goods and the growing human population result in increasing amounts of various wastes, including tailings. The mining industry in Poland, comprising also mining of non-ferrous metal ores, is a strategic branch of the national economy and at the same time a leading waste producer. Tailings management is a significant problem both in Poland and worldwide. Frequently considerable amounts of wastes are accumulated in mine spoil tips, in areas not always suitable for their deposition, thus leading to the degradation of the surrounding environment. At the huge volume of produced wastes their rational and economically viable management is becoming crucial. On the other hand, depletion of natural aggregate deposits is an important incentive to search for substitutes, which would be suitable for the development of road infrastructure or which could be used in earth structure engineering to construct hydroengineering objects. Since no profitable recovery technologies are available at present, tailings generated by copper mining are deposited in tailings storage facilities. The largest and at the same time the only currently operating facility in Poland is the Żelazny Most Mining Tailings Storage Facility, belonging to KGHM Polska Miedź S.A. The paper presents criteria for material quality and density imposed on the material embedded in the static core of the tailings pond dam. For this purpose studies were conducted to confirm applicability of sorted tailings as a material for the construction of earth structures.

  16. Artificial inoculation-perspectives in tailings phytostabilization.

    Science.gov (United States)

    Petrisor, Ioana G; Dobrota, Smaranda; Komnitsas, Kostas; Lazar, Ioan; Kuperberg, J Michael; Serban, Mihai

    2004-01-01

    Intensive mining and processing activities worldwide resulted in the generation of huge amounts of waste (tailings), generally characterized as toxic, radioactive, and/or hazardous. The exposure potential and, hence, the risk posed by such wastes is enhanced by a general lack of vegetation. Phytostabilization has proven to be efficient in reducing this risk. However, establishing vegetation on tailing dumps may be expensive due to the intensive use of amendments and chemical fertilizers. In this article, investigations on artificial inoculation of mine tailings with bacterial strains as a means to improve the development of vegetative covers and reduce application cost by eliminating chemical fertilization are presented and discussed. The development of plants and microbial communities from tailings, as well as the impact of inoculation on metal uptake in plants, were studied. Experiments were carried out in greenhouse using two types of mine tailings (phosphogypsum and sulphidic tailings) from the Romanian Black Sea coast. Indigenous herbaceous plants were cultivated on tailings with the addition of chemical fertilizers versus bacterial inoculation. After a 6-month experimental period, excellent plant growth, which is associated with a rich microbial community, was observed in all inoculated treatments, in contrast with poor plant growth and microbiota from the chemical fertilization treatments alone. Additionally, artificial inoculation improved plant resistance to heavy metals by reducing the uptake of some toxic metals. Once a rich microbial community is established, inoculation may be discontinued. Based on these results, efficient and cost-effective phytostabilization schemes can be proposed.

  17. POTAMOS mass spectrometry calculator: computer aided mass spectrometry to the post-translational modifications of proteins. A focus on histones.

    Science.gov (United States)

    Vlachopanos, A; Soupsana, E; Politou, A S; Papamokos, G V

    2014-12-01

    Mass spectrometry is a widely used technique for protein identification and it has also become the method of choice in order to detect and characterize the post-translational modifications (PTMs) of proteins. Many software tools have been developed to deal with this complication. In this paper we introduce a new, free and user friendly online software tool, named POTAMOS Mass Spectrometry Calculator, which was developed in the open source application framework Ruby on Rails. It can provide calculated mass spectrometry data in a time saving manner, independently of instrumentation. In this web application we have focused on a well known protein family of histones whose PTMs are believed to play a crucial role in gene regulation, as suggested by the so called "histone code" hypothesis. The PTMs implemented in this software are: methylations of arginines and lysines, acetylations of lysines and phosphorylations of serines and threonines. The application is able to calculate the kind, the number and the combinations of the possible PTMs corresponding to a given peptide sequence and a given mass along with the full set of the unique primary structures produced by the possible distributions along the amino acid sequence. It can also calculate the masses and charges of a fragmented histone variant, which carries predefined modifications already implemented. Additional functionality is provided by the calculation of the masses of fragments produced upon protein cleavage by the proteolytic enzymes that are most widely used in proteomics studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Tail posture predicts tail biting outbreaks at pen level in weaner pigs

    DEFF Research Database (Denmark)

    Lahrmann, Helle Pelant; Hansen, Christian Fink; D'Eath, Rick

    2018-01-01

    :00 h-14:00 h from weaning until a tail biting outbreak. An outbreak (day 0) occurred when at least four pigs had a tail damage, regardless of wound freshness. On average 7.6 (SD 4.3) pigs had a damaged tail (scratches + wound) in T-pens on day 0. Tail posture and behaviour (activity, eating......, explorative, pen mate and tail directed behaviour) were recorded in T-pens and in matched C-pens using scan sampling every half hour between 0800-1100 h 1700-2000 h on day -3, -2 and -1 prior to the tail biting outbreak in T-pens. Further, to investigate if changes in tail posture could be a measure for use...... under commercial conditions, tail posture was recorded by direct observation from outside the pen. The live observations were carried out just before tail scoring on each observation day until the outbreak. The video results showed more hanging/tucked tails in T-pens than in C-pens on each recording day...

  19. Variation in salamander tail regeneration is associated with genetic factors that determine tail morphology.

    Directory of Open Access Journals (Sweden)

    Gareth J Voss

    Full Text Available Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander's tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66-68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (<4% and correlated with tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site.

  20. Variation in salamander tail regeneration is associated with genetic factors that determine tail morphology.

    Science.gov (United States)

    Voss, Gareth J; Kump, D Kevin; Walker, John A; Voss, S Randal

    2013-01-01

    Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni) was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander's tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66-68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site.

  1. Hovercraft drill probes Saraji tailings dam

    Energy Technology Data Exchange (ETDEWEB)

    1991-09-01

    In early operations at BHP-Utah's Saraji Mine in central Queensland, quantities of coking coal were pumped into the tailings dam because the preparation plant's flotation circuit was unable to handle ultra-fines. A reverse circulating drilling rig mounted on a hovercraft was used to recover 22 samples (representing 9 metres of tailings from 11 x 8 x 0.09 metre cores) in an investigation into whether the tailings can now be treated economically. 1 fig.

  2. Moulting tail feathers in a juvenile oviraptorisaur.

    Science.gov (United States)

    Prum, Richard O

    2010-11-04

    Xu et al. describe the extraordinarily preserved feathers from two subadults of the oviraptorisaur Similicaudipteryx from the Yixian Formation of Liaoning, China. The preserved tail feathers of the juvenile specimen (STM4.1) show a morphology not previously observed in any fossil feathers. The tail feathers of an older, immature specimen (STM22-6) show a typical closed pennaceous structure with a prominent, planar vane. I propose that the feathers of the tail of the juvenile specimen are not a specialized feather generation, but fossilized 'pin feathers' or developing feather germs.

  3. Role of the acidic tail of high mobility group protein B1 (HMGB1) in protein stability and DNA bending.

    Science.gov (United States)

    Belgrano, Fabricio S; de Abreu da Silva, Isabel C; Bastos de Oliveira, Francisco M; Fantappié, Marcelo R; Mohana-Borges, Ronaldo

    2013-01-01

    High mobility group box (HMGB) proteins are abundant nonhistone proteins found in all eukaryotic nuclei and are capable of binding/bending DNA. The human HMGB1 is composed of two binding motifs, known as Boxes A and B, are L-shaped alpha-helix structures, followed by a random-coil acidic tail that consists of 30 Asp and Glu residues. This work aimed at evaluating the role of the acidic tail of human HMGB1 in protein stability and DNA interactions. For this purpose, we cloned, expressed and purified HMGB1 and its tailless form, HMGB1ΔC, in E. coli strain. Tryptophan fluorescence spectroscopy and circular dichroism (CD) experiments clearly showed an increase in protein stability promoted by the acidic tail under different conditions, such as the presence of the chemical denaturant guanidine hydrochloride (Gdn.HCl), high temperature and low pH. Folding intermediates found at low pH for both proteins were denatured only in the presence of chemical denaturant, thus showing a relatively high stability. The acidic tail did not alter the DNA-binding properties of the protein, although it enhanced the DNA bending capability from 76° (HMGB1ΔC) to 91° (HMGB1), as measured using the fluorescence resonance energy transfer technique. A model of DNA bending in vivo was proposed, which might help to explain the interaction of HMGB1 with DNA and other proteins, i.e., histones, and the role of that protein in chromatin remodeling.

  4. The DNA-repair Ku70 protein is located in the nucleus and tail of elongating spermatids in grasshoppers.

    Science.gov (United States)

    Cabrero, Josefa; Palomino-Morales, Rogelio J; Camacho, Juan Pedro M

    2007-01-01

    Fluorescence immunostaining for the phosphorylated H2AX histone (gammaH2AX) in the grasshopper Eyprepocnemis plorans has shown abundance of gammaH2AX in the nuclei of round and elongating spermatids, suggesting that DNA double-strand breaks (DSBs) occur regularly during spermiogenesis. Immunofluorescence patterns for Ku70, a DNA-repair protein participating in the non-homologous end-joining (NHEJ) pathway, showed that this protein is present in round and elongating spermatids, implying that the NHEJ DNA-repair pathway operates during chromatin compaction in spermiogenesis. In addition, during the final stages of spermiogenesis, the Ku70 protein concentrates on the region forming the sperm tail. Since Ku70 was also abundant in spermatid tails, it is reasonable to assume that Ku70 might play a novel function in sperm-tail formation. The analysis of Ku70 immunofluorescence patterns in 13 other grasshopper species also showed the presence of this protein in the nucleus and tail of elongating spermatids, indicating that this is a general characteristic in grasshoppers.

  5. An evaluation procedure for flocculation of coal preparation plant tailings.

    Science.gov (United States)

    Sabah, E; Cengiz, I

    2004-03-01

    In solid-liquid separation of coal preparation plant tailings by flocculation, in addition to the type and amount of flocculants, the composition of waste materials including clay minerals must be determined in order to devise an effective and economic sedimentation system. In this study, the characterization of organic and inorganic impurities was made with the help of mineralogical data and instrumental analysis techniques. The effects of polymer type (medium and low anionic, cationic and nonionic), polymer dosage and suspension pH on flocculation mechanism of tailings particles (-0.18 mm) in the Tunçbilek Coal Preparation Plant tailings of Tunçbilek (Turkey) were investigated. Medium anionic polymer accelerated the settling rate of particles. An optimum settling rate (300 mm/min) was reached at a dosage rate of 34.19 g/ton-solids (2.0 mg/l), 51.28 g/ton-solids (3.0 mg/l), 102.56 g/ton-solids (6.0 mg/l) and 119.66 g/ton-solids (7.0mg/l) for medium anionic, low charged anionic, nonionic and cationic polymers, respectively. The lowest turbidity values at low polymer dosages were obtained by the cationic polymer at around 25.64 g/ton-solids (1.5 mg/l) polymer dosages; however, the low anionic and nonionic polymers produced lower turbidity values at higher dosages (>25.64 g/ton-solids). At optimum dosages of the polymer, the settling rate decreased at low and high pHs indicating that the natural pH (pH 8.3) of the suspension is the most appropriate pH for the settling rate. On the other hand, the water clarity values at natural pHs were high for all of the polymers.

  6. Interaction of oil sands tailings particles with polymers and microbial cells: First steps toward reclamation to soil.

    Science.gov (United States)

    Voordouw, Gerrit

    2013-04-01

    Production of bitumen by surface mining of Alberta's oil sands has given rise to tailings ponds, containing large volumes of finely dispersed clays (10(8) m(3)), which settle only slowly. The mature fine tailings (MFT) in these ponds are operationally defined as consisting of particles smaller than 44 μm with a solids content in excess of 30% (w/w). Increasing the rate of densification of MFT is a rate-limiting step in tailings pond reclamation. Accelerated densification has been achieved through mixing of MFT with sand in the presence of calcium sulfate as a binding agent to generate consolidated tailings. Addition of negatively charged polymer, together with either calcium or magnesium ions, is similarly effective. Although toxic to higher aquatic life, tailings ponds harbour a wide variety of mainly anaerobic microbes. These convert residual hydrocarbon, causing methane emissions of up to 10(4) m(3) day(-1). Interestingly, anaerobic microbial activity also accelerates tailings pond densification. Hence, many technologies designed to accelerate densification move tailings, at least conceptually, towards soil in which sand and clay particles are linked by large amounts of humic and fulvic acid polymers supporting large numbers of microbes in a mechanically stable structure. Copyright © 2012 Wiley Periodicals, Inc.

  7. Expressed Centromere Specific Histone 3 (CENH3 Variants in Cultivated Triploid and Wild Diploid Bananas (Musa spp.

    Directory of Open Access Journals (Sweden)

    Kariuki S. Muiruri

    2017-06-01

    Full Text Available Centromeres are specified by a centromere specific histone 3 (CENH3 protein, which exists in a complex environment, interacting with conserved proteins and rapidly evolving satellite DNA sequences. The interactions may become more challenging if multiple CENH3 versions are introduced into the zygote as this can affect post-zygotic mitosis and ultimately sexual reproduction. Here, we characterize CENH3 variant transcripts expressed in cultivated triploid and wild diploid progenitor bananas. We describe both splice- and allelic-[Single Nucleotide Polymorphisms (SNP] variants and their effects on the predicted secondary structures of protein. Expressed CENH3 transcripts from six banana genotypes were characterized and clustered into three groups (MusaCENH-1A, MusaCENH-1B, and MusaCENH-2 based on similarity. The CENH3 groups differed with SNPs as well as presence of indels resulting from retained and/or skipped exons. The CENH3 transcripts from different banana genotypes were spliced in either 7/6, 5/4 or 6/5 exons/introns. The 7/6 and the 5/4 exon/intron structures were found in both diploids and triploids, however, 7/6 was most predominant. The 6/5 exon/introns structure was a result of failure of the 7/6 to splice correctly. The various transcripts obtained were predicted to encode highly variable N-terminal tails and a relatively conserved C-terminal histone fold domain (HFD. The SNPs were predicted in some cases to affect the secondary structure of protein by lengthening or shorting the affected domains. Sequencing of banana CENH3 transcripts predicts SNP variations that affect amino acid sequences and alternatively spliced transcripts. Most of these changes affect the N-terminal tail of CENH3.

  8. Conservation and divergence of the histone code in nucleomorphs.

    Science.gov (United States)

    Marinov, Georgi K; Lynch, Michael

    2016-04-05

    Nucleomorphs, the remnant nuclei of photosynthetic algae that have become endosymbionts to other eukaryotes, represent a unique example of convergent reductive genome evolution in eukaryotes, having evolved independently on two separate occasions in chlorarachniophytes and cryptophytes. The nucleomorphs of the two groups have evolved in a remarkably convergent manner, with numerous very similar features. Chief among them is the extreme reduction and compaction of nucleomorph genomes, with very small chromosomes and extremely short or even completely absent intergenic spaces. These characteristics pose a number of intriguing questions regarding the mechanisms of transcription and gene regulation in such a crowded genomic context, in particular in terms of the functioning of the histone code, which is common to almost all eukaryotes and plays a central role in chromatin biology. This study examines the sequences of nucleomorph histone proteins in order to address these issues. Remarkably, all classical transcription- and repression-related components of the histone code seem to be missing from chlorarachniophyte nucleomorphs. Cryptophyte nucleomorph histones are generally more similar to the conventional eukaryotic state; however, they also display significant deviations from the typical histone code. Based on the analysis of specific components of the code, we discuss the state of chromatin and the transcriptional machinery in these nuclei. The results presented here shed new light on the mechanisms of nucleomorph transcription and gene regulation and provide a foundation for future studies of nucleomorph chromatin and transcriptional biology.

  9. The Functional Analysis of Histone Acetyltransferase MOF in Tumorigenesis.

    Science.gov (United States)

    Su, Jiaming; Wang, Fei; Cai, Yong; Jin, Jingji

    2016-01-14

    Changes in chromatin structure and heritably regulating the gene expression by epigenetic mechanisms, such as histone post-translational modification, are involved in most cellular biological processes. Thus, abnormal regulation of epigenetics is implicated in the occurrence of various diseases, including cancer. Human MOF (males absent on the first) is a member of the MYST (Moz-Ybf2/Sas3-Sas2-Tip60) family of histone acetyltransferases (HATs). As a catalytic subunit, MOF can form at least two distinct multiprotein complexes (MSL and NSL) in human cells. Both complexes can acetylate histone H4 at lysine 16 (H4K16); however, the NSL complex possesses broader substrate specificity and can also acetylate histone H4 at lysines 5 and 8 (H4K5 and H4K8), suggesting the complexity of the intracellular functions of MOF. Silencing of MOF in cells leads to genomic instability, inactivation of gene transcription, defective DNA damage repair and early embryonic lethality. Unbalanced MOF expression and its corresponding acetylation of H4K16 have been found in certain primary cancer tissues, including breast cancer, medulloblastoma, ovarian cancer, renal cell carcinoma, colorectal carcinoma, gastric cancer, as well as non-small cell lung cancer. In this review, we provide a brief overview of MOF and its corresponding histone acetylation, introduce recent research findings that link MOF functions to tumorigenesis and speculate on the potential role that may be relevant to tumorigenic pathways.

  10. The Functional Analysis of Histone Acetyltransferase MOF in Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jiaming Su

    2016-01-01

    Full Text Available Changes in chromatin structure and heritably regulating the gene expression by epigenetic mechanisms, such as histone post-translational modification, are involved in most cellular biological processes. Thus, abnormal regulation of epigenetics is implicated in the occurrence of various diseases, including cancer. Human MOF (males absent on the first is a member of the MYST (Moz-Ybf2/Sas3-Sas2-Tip60 family of histone acetyltransferases (HATs. As a catalytic subunit, MOF can form at least two distinct multiprotein complexes (MSL and NSL in human cells. Both complexes can acetylate histone H4 at lysine 16 (H4K16; however, the NSL complex possesses broader substrate specificity and can also acetylate histone H4 at lysines 5 and 8 (H4K5 and H4K8, suggesting the complexity of the intracellular functions of MOF. Silencing of MOF in cells leads to genomic instability, inactivation of gene transcription, defective DNA damage repair and early embryonic lethality. Unbalanced MOF expression and its corresponding acetylation of H4K16 have been found in certain primary cancer tissues, including breast cancer, medulloblastoma, ovarian cancer, renal cell carcinoma, colorectal carcinoma, gastric cancer, as well as non-small cell lung cancer. In this review, we provide a brief overview of MOF and its corresponding histone acetylation, introduce recent research findings that link MOF functions to tumorigenesis and speculate on the potential role that may be relevant to tumorigenic pathways.

  11. Single-nucleosome mapping of histone modifications in S. cerevisiae.

    Directory of Open Access Journals (Sweden)

    Chih Long Liu

    2005-10-01

    Full Text Available Covalent modification of histone proteins plays a role in virtually every process on eukaryotic DNA, from transcription to DNA repair. Many different residues can be covalently modified, and it has been suggested that these modifications occur in a great number of independent, meaningful combinations. Published low-resolution microarray studies on the combinatorial complexity of histone modification patterns suffer from confounding effects caused by the averaging of modification levels over multiple nucleosomes. To overcome this problem, we used a high-resolution tiled microarray with single-nucleosome resolution to investigate the occurrence of combinations of 12 histone modifications on thousands of nucleosomes in actively growing S. cerevisiae. We found that histone modifications do not occur independently; there are roughly two groups of co-occurring modifications. One group of lysine acetylations shows a sharply defined domain of two hypo-acetylated nucleosomes, adjacent to the transcriptional start site, whose occurrence does not correlate with transcription levels. The other group consists of modifications occurring in gradients through the coding regions of genes in a pattern associated with transcription. We found no evidence for a deterministic code of many discrete states, but instead we saw blended, continuous patterns that distinguish nucleosomes at one location (e.g., promoter nucleosomes from those at another location (e.g., over the 3' ends of coding regions. These results are consistent with the idea of a simple, redundant histone code, in which multiple modifications share the same role.

  12. Workplace Charging. Charging Up University Campuses

    Energy Technology Data Exchange (ETDEWEB)

    Giles, Carrie [ICF International, Fairfax, VA (United States); Ryder, Carrie [ICF International, Fairfax, VA (United States); Lommele, Stephen [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2016-03-01

    This case study features the experiences of university partners in the U.S. Department of Energy's (DOE) Workplace Charging Challenge with the installation and management of plug-in electric vehicle (PEV) charging stations.

  13. How do birds' tails work? Delta-wing theory fails to predict tail shape during flight.

    Science.gov (United States)

    Evans, Matthew R; Rosén, Mikael; Park, Kirsty J; Hedenström, Anders

    2002-05-22

    Birds appear to use their tails during flight, but until recently the aerodynamic role that tails fulfil was largely unknown. In recent years delta-wing theory, devised to predict the aerodynamics of high-performance aircraft, has been applied to the tails of birds and has been successful in providing a model for the aerodynamics of a bird's tail. This theory now provides the conventional explanation for how birds' tails work. A delta-wing theory (slender-wing theory) has been used, as part of a variable-geometry model to predict how tail and wing shape should vary during flight at different airspeeds. We tested these predictions using barn swallows flying in a wind tunnel. We show that the predictions are not quantitatively well supported. This suggests that a new theory or a modified version of delta-wing theory is needed to adequately explain the way in which morphology varies during flight.

  14. The histone-fold complex MHF is remodeled by FANCM to recognize branched DNA and protect genome stability.

    Science.gov (United States)

    Fox, David; Yan, Zhijiang; Ling, Chen; Zhao, Ye; Lee, Duck-Yeon; Fukagawa, Tatsuo; Yang, Wei; Wang, Weidong

    2014-05-01

    Histone-fold proteins typically assemble in multiprotein complexes to bind duplex DNA. However, one histone-fold complex, MHF, associates with Fanconi anemia (FA) protein FANCM to form a branched DNA remodeling complex that senses and repairs stalled replication forks and activates FA DNA damage response network. How the FANCM-MHF complex recognizes branched DNA is unclear. Here, we solved the crystal structure of MHF and its complex with the MHF-interaction domain (referred to as MID) of FANCM, and performed structure-guided mutagenesis. We found that the MID-MHF complex consists of one histone H3-H4-like MHF heterotetramer wrapped by a single polypeptide of MID. We identified a zinc atom-liganding structure at the central interface between MID and MHF that is critical for stabilization of the complex. Notably, the DNA-binding surface of MHF was altered by MID in both electrostatic charges and allosteric conformation. This leads to a switch in the DNA-binding preference - from duplex DNA by MHF alone, to branched DNA by the MID-MHF complex. Mutations that disrupt either the composite DNA-binding surface or the protein-protein interface of the MID-MHF complex impaired activation of the FA network and genome stability. Our data provide the structural basis of how FANCM and MHF work together to recognize branched DNA, and suggest a novel mechanism by which histone-fold complexes can be remodeled by their partners to bind special DNA structures generated during DNA metabolism.

  15. BIOMECHANICS. Why the seahorse tail is square.

    Science.gov (United States)

    Porter, Michael M; Adriaens, Dominique; Hatton, Ross L; Meyers, Marc A; McKittrick, Joanna

    2015-07-03

    Whereas the predominant shapes of most animal tails are cylindrical, seahorse tails are square prisms. Seahorses use their tails as flexible grasping appendages, in spite of a rigid bony armor that fully encases their bodies. We explore the mechanics of two three-dimensional-printed models that mimic either the natural (square prism) or hypothetical (cylindrical) architecture of a seahorse tail to uncover whether or not the square geometry provides any functional advantages. Our results show that the square prism is more resilient when crushed and provides a mechanism for preserving articulatory organization upon extensive bending and twisting, as compared with its cylindrical counterpart. Thus, the square architecture is better than the circular one in the context of two integrated functions: grasping ability and crushing resistance. Copyright © 2015, American Association for the Advancement of Science.

  16. A Tale of Axillary Tail of Breast

    Directory of Open Access Journals (Sweden)

    Smita Sankaye

    2014-06-01

    Full Text Available This original article tells the tale of the axillary tail of the breast. Although often neglected, it can be the cause of tumor or tension. Human breast`s parenchymal extension into the axilla is known as the axillary tail of the breast. Normally, it remains confined as per the healthy individual's body habitus. But sometimes it may become prominent and thereby a cause of tension.A plethora of findings have been reported to occur in an axillary tail. From toxoplasma to tumors, the list is comprehensive. Hence, each individual with a prominent axillary tail has its own tale to tell as has been explained in this article. Pathologists as well as Radiologists should be well aware of the various normal and abnormal entities affecting it, so that the distressed individual seeking assistance is properly managed. [Cukurova Med J 2014; 39(3.000: 540-545

  17. Unique structural features facilitate lizard tail autotomy.

    Directory of Open Access Journals (Sweden)

    Kristian W Sanggaard

    Full Text Available Autotomy refers to the voluntary shedding of a body part; a renowned example is tail loss among lizards as a response to attempted predation. Although many aspects of lizard tail autotomy have been studied, the detailed morphology and mechanism remains unclear. In the present study, we showed that tail shedding by the Tokay gecko (Gekko gecko and the associated extracellular matrix (ECM rupture were independent of proteolysis. Instead, lizard caudal autotomy relied on biological adhesion facilitated by surface microstructures. Results based on bio-imaging techniques demonstrated that the tail of Gekko gecko was pre-severed at distinct sites and that its structural integrity depended on the adhesion between these segments.

  18. Physical space and long-tail markets

    Science.gov (United States)

    Bentley, R. Alexander; Madsen, Mark E.; Ormerod, Paul

    2009-03-01

    The Internet is known to have had a powerful impact on on-line retailer strategies in markets characterised by long-tail distribution of sales [C. Anderson, Long Tail: Why the Future of Business is Selling Less of More, Hyperion, New York, 2006]. Such retailers can exploit the long tail of the market, since they are effectively without physical limit on the number of choices on offer. Here we examine two extensions of this phenomenon. First, we introduce turnover into the long-tail distribution of sales. Although over any given period such as a week or a month, the distribution is right-skewed and often power law distributed, over time there is considerable turnover in the rankings of sales of individual products. Second, we establish some initial results on the implications for shelf-space and physical retailers in such markets.

  19. Suncor south tailings pond research program : geotechnical investigations

    Energy Technology Data Exchange (ETDEWEB)

    Holden, A. [Suncor Energy Inc. Oil Sands, Fort McMurray, AB (Canada)

    2009-07-01

    This study investigated the geochemical impact of seepage from an oil sands tailings impoundment on sediments and groundwater resources at Suncor Energy's south tailings pond. The study examined the potential for attenuation of inorganic contaminants and trace metal releases. Binding capacity was investigated in relation to seepage interactions with native sediments. Cations displaced through interactions with ingressing process water were characterized. The study hypothesized that ion sorption affinity was governed by ion charge; size; properties of the solid exchanger; the quantity and ratios of the various solutes; and the total solution concentration. Batch sorption studies were conducted to investigate the effects of adsorptive and ion exchange reactions on the mitigation and mobilization of major cations and trace metals. Models were designed to simulated the capture system behaviour of most major cations. The study demonstrated that the sodium (Na) will replace calcium (Ca) and magnesium (Mg) and precipitate out as CO{sub 3} salts. It was concluded that the ion exchange theory offers a suitable explanation of Ca and Mg system behaviour. tabs., figs.

  20. Shake a Tail Feather: The Evolution of the Theropod Tail into a Stiff Aerodynamic Surface

    Science.gov (United States)

    Pittman, Michael; Gatesy, Stephen M.; Upchurch, Paul; Goswami, Anjali; Hutchinson, John R.

    2013-01-01

    Theropod dinosaurs show striking morphological and functional tail variation; e.g., a long, robust, basal theropod tail used for counterbalance, or a short, modern avian tail used as an aerodynamic surface. We used a quantitative morphological and functional analysis to reconstruct intervertebral joint stiffness in the tail along the theropod lineage to extant birds. This provides new details of the tail’s morphological transformation, and for the first time quantitatively evaluates its biomechanical consequences. We observe that both dorsoventral and lateral joint stiffness decreased along the non-avian theropod lineage (between nodes Theropoda and Paraves). Our results show how the tail structure of non-avian theropods was mechanically appropriate for holding itself up against gravity and maintaining passive balance. However, as dorsoventral and lateral joint stiffness decreased, the tail may have become more effective for dynamically maintaining balance. This supports our hypothesis of a reduction of dorsoventral and lateral joint stiffness in shorter tails. Along the avian theropod lineage (Avialae to crown group birds), dorsoventral and lateral joint stiffness increased overall, which appears to contradict our null expectation. We infer that this departure in joint stiffness is specific to the tail’s aerodynamic role and the functional constraints imposed by it. Increased dorsoventral and lateral joint stiffness may have facilitated a gradually improved capacity to lift, depress, and swing the tail. The associated morphological changes should have resulted in a tail capable of producing larger muscular forces to utilise larger lift forces in flight. Improved joint mobility in neornithine birds potentially permitted an increase in the range of lift force vector orientations, which might have improved flight proficiency and manoeuvrability. The tail morphology of modern birds with tail fanning capabilities originated in early ornithuromorph birds. Hence

  1. Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-kappa B-mediated inflammation

    NARCIS (Netherlands)

    Leus, Niek G. J.; Zwinderman, Martijn R. H.; Dekker, Frank J.

    Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications is lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing

  2. Electrodialytic Remediation of Copper Mine Tailings

    DEFF Research Database (Denmark)

    Hansen, H.K.; Rojo, A.; Ottosen, L.M.

    2012-01-01

    This work compares and evaluates sixteen electrodialytic laboratory remediation experiments on copper mine tailings. Different parameters were analysed, such as remediation time, addition of desorbing agents, and the use of pulsed electrical fields.......This work compares and evaluates sixteen electrodialytic laboratory remediation experiments on copper mine tailings. Different parameters were analysed, such as remediation time, addition of desorbing agents, and the use of pulsed electrical fields....

  3. Unique structural features facilitate lizard tail autotomy

    DEFF Research Database (Denmark)

    Sanggaard, Kristian W; Danielsen, Carl Chr; Wogensen, Lise

    2012-01-01

    that tail shedding by the Tokay gecko (Gekko gecko) and the associated extracellular matrix (ECM) rupture were independent of proteolysis. Instead, lizard caudal autotomy relied on biological adhesion facilitated by surface microstructures. Results based on bio-imaging techniques demonstrated that the tail...... of Gekko gecko was pre-severed at distinct sites and that its structural integrity depended on the adhesion between these segments....

  4. Identifying the Combinatorial Effects of Histone Modifications by Association Rule Mining in Yeast

    Science.gov (United States)

    Wang, Jiang; Dai, Xianhua; Xiang, Qian; Deng, Yangyang; Feng, Jihua; Dai, Zhiming; He, Caisheng

    2010-01-01

    Eukaryotic genomes are packaged into chromatin by histone proteins whose chemical modification can profoundly influence gene expression. The histone modifications often act in combinations, which exert different effects on gene expression. Although a number of experimental techniques and data analysis methods have been developed to study histone modifications, it is still very difficult to identify the relationships among histone modifications on a genome-wide scale. We proposed a method to identify the combinatorial effects of histone modifications by association rule mining. The method first identified Functional Modification Transactions (FMTs) and then employed association rule mining algorithm and statistics methods to identify histone modification patterns. We applied the proposed methodology to Pokholok et al’s data with eight sets of histone modifications and Kurdistani et al’s data with eleven histone acetylation sites. Our method succeeds in revealing two different global views of histone modification landscapes on two datasets and identifying a number of modification patterns some of which are supported by previous studies. We concentrate on combinatorial effects of histone modifications which significantly affect gene expression. Our method succeeds in identifying known interactions among histone modifications and uncovering many previously unknown patterns. After in-depth analysis of possible mechanism by which histone modification patterns can alter transcriptional states, we infer three possible modification pattern reading mechanism (‘redundant’, ‘trivial’, ‘dominative’). Our results demonstrate several histone modification patterns which show significant correspondence between yeast and human cells. PMID:21037963

  5. Microbiology could help clean up tailings ponds

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    2010-09-15

    This article reported on the discovery that populations of nitrate-reducing bacteria can promote sedimentation in oilsands tailings ponds and can at the same time reduce the production and release of harmful methane gas and allow more water from the ponds to be recycled, thereby lessening the amount of fresh water needed for the oil-extraction process. The evidence that this class of micro-organism contributes to tailings sedimentation opens up new possibilities for the future management of tailings ponds and the reduction of tailings pond toxicity. Methanogenic bacteria were already known to participate in tailings pond densification, but these organisms produce undesirable methane gas as a byproduct. Larger-scale experiments are needed to validate the laboratory results before appropriate field-scale applications can be designed. The findings could potentially lead to technologies that help oil sands companies reclaim land more effectively and in a shorter period of time. Microbiology was deemed to be an important aspect of tailings management. 1 ref.

  6. The Sodium Tail of the Moon

    Science.gov (United States)

    Matta, M.; Smith, S.; Baumgardner, J.; Wilson, J.; Martinis, C.; Mendillo, M.

    2009-01-01

    During the few days centered about new Moon, the lunar surface is optically hidden from Earth-based observers. However, the Moon still offers an observable: an extended sodium tail. The lunar sodium tail is the escaping "hot" component of a coma-like exosphere of sodium generated by photon-stimulated desorption, solar wind sputtering and meteoroid impact. Neutral sodium atoms escaping lunar gravity experience solar radiation pressure that drives them into the anti-solar direction forming a comet-like tail. During new Moon time, the geometry of the Sun, Moon and Earth is such that the anti-sunward sodium flux is perturbed by the terrestrial gravitational field resulting in its focusing into a dense core that extends beyond the Earth. An all-sky camera situated at the El Leoncito Observatory (CASLEO) in Argentina has been successfully imaging this tail through a sodium filter at each lunation since April 2006. This paper reports on the results of the brightness of the lunar sodium tail spanning 31 lunations between April 2006 and September 2008. Brightness variability trends are compared with both sporadic and shower meteor activity, solar wind proton energy flux and solar near ultra violet (NUV) patterns for possible correlations. Results suggest minimal variability in the brightness of the observed lunar sodium tail, generally uncorrelated with any single source, yet consistent with a multi-year period of minimal solar activity and non-intense meteoric fluxes.

  7. Quantitative Histone Mass Spectrometry Identifies Elevated Histone H3 Lysine 27 (Lys27) Trimethylation in Melanoma.

    Science.gov (United States)

    Sengupta, Deepanwita; Byrum, Stephanie D; Avaritt, Nathan L; Davis, Lauren; Shields, Bradley; Mahmoud, Fade; Reynolds, Matthew; Orr, Lisa M; Mackintosh, Samuel G; Shalin, Sara C; Tackett, Alan J

    2016-03-01

    Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post-translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys(27) trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E-cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Structure and activity of enzymes that remove histone modifications.

    Science.gov (United States)

    Holbert, Marc A; Marmorstein, Ronen

    2005-12-01

    The post-translational modification of histones plays an important role in chromatin regulation, a process that insures the fidelity of gene expression and other DNA transactions. Equally important as the enzymes that generate these modifications are the enzymes that remove them. Recent studies have identified some of the enzymes that remove histone modifications and have characterized their activities. In addition, structural and biochemical studies of these enzymes have focused on the histone lysine deacetylases HDAC8 and sirtuins, and on the arginine and lysine demethylases PAD and BHC110/LSD1, respectively. These new findings may be used as a context to present new information that contributes to our understanding of chromatin regulation, and to pose remaining questions pertaining to the activities of these enzymes and the roles they play in chromatin regulation.

  9. Sliding and peeling of histone during chromatin remodelling

    CERN Document Server

    Garai, Ashok; Chowdhury, Debashish

    2011-01-01

    ATP-dependent chromatin remodeling enzymes (CRE) are bio-molecular motors in eukaryotic cells. These are driven by a chemical fuel, namely, adenosine triphosphate (ATP). CREs actively participate in many cellular processes that require accessibility of specific stretches of DNA which are packaged as chromatin. The basic unit of chromatin is a nucleosome where 146 bp $\\sim$ 50 nm of a double stranded DNA (dsDNA) is wrapped around a spool formed by histone proteins. We investigate the mechanism of peeling of the histone spool, and its complete detachment, from the dsDNA by a CRE. Our two-state model of a CRE captures effectively two distinct chemical (or conformational) states in the mechano-chemical cycle of each ATP-dependent CRE. We calculate the mean times for histone detachment. Our predictions on the ATP-dependence of the measurable quantities can be tested by carrying out {\\it in-vitro} experiments.

  10. The Histone Modification Code in the Pathogenesis of Autoimmune Diseases.

    Science.gov (United States)

    Araki, Yasuto; Mimura, Toshihide

    2017-01-01

    Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes.

  11. The Histone Modification Code in the Pathogenesis of Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Yasuto Araki

    2017-01-01

    Full Text Available Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes.

  12. Low Proteolytic Clipping of Histone H3 in Cervical Cancer

    Science.gov (United States)

    Sandoval-Basilio, Jorge; Serafín-Higuera, Nicolás; Reyes-Hernandez, Octavio D.; Serafín-Higuera, Idanya; Leija-Montoya, Gabriela; Blanco-Morales, Magali; Sierra-Martínez, Monica; Ramos-Mondragon, Roberto; García, Silvia; López-Hernández, Luz Berenice; Yocupicio-Monroy, Martha; Alcaraz-Estrada, Sofia L.

    2016-01-01

    Chromatin in cervical cancer (CC) undergoes chemical and structural changes that alter the expression pattern of genes. Recently, a potential mechanism, which regulates gene expression at transcriptional levels is the proteolytic clipping of histone H3. However, until now this process in CC has not been reported. Using HeLa cells as a model of CC and human samples from patients with CC, we identify that the H3 cleavage was lower in CC compared with control tissue. Additionally, the histone H3 clipping was performed by serine and aspartyl proteases in HeLa cells. These results suggest that histone H3 clipping operates as part of post-translational modification system in CC. PMID:27698925

  13. The role of histone methyltransferase EZH2 in myelodysplastic syndromes.

    Science.gov (United States)

    Xu, Feng; Li, Xiao

    2012-04-01

    Previous epigenetics research in myelodysplastic syndromes (MDS) mainly focused on the DNA methylation of tumor suppressor genes. Recent studies reported that around 6% of MDS patients have several EZH2 mutations including missense, frameshift and truncated mutations. Histone methyltransferase EZH2 plays a critical role in epigenetic regulation as a bridge between histone methylation/deacetylation and DNA methylation. EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival. Many questions still need further discussion. Moreover, 3-deazaneplanocin can reduce EZH2 levels and H3K27 trimethylation, and synergistic effects are seen in combination with DNA demethylation agents or histone deacetylation inhibitors. All of the above give us more chances to improve epigenetic therapy in MDS. Therefore, the molecular mechanisms of EZH2 in tumorigenesis and the role of EZH2 in MDS are studied.

  14. Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis

    Directory of Open Access Journals (Sweden)

    Frederic eLamoth

    2015-02-01

    Full Text Available Invasive aspergillosis (IA is a life-threatening infection due to Aspergillus fumigatus and other Aspergillus spp. Drugs targeting the fungal cell membrane (triazoles, amphotericin B or cell wall (echinocandins are currently the sole therapeutic options against IA. Their limited efficacy and the emergence of resistance warrant the identification of new antifungal targets. Histone deacetylases (HDACs are enzymes responsible of the deacetylation of lysine residues of core histones, thus controlling chromatin remodeling and transcriptional activation. HDACs also control the acetylation and activation status of multiple non-histone proteins, including the heat shock protein 90 (Hsp90, an essential molecular chaperone for fungal virulence and antifungal resistance. This review provides an overview of the different HDACs in Aspergillus spp. as well as their respective contribution to total HDAC activity, fungal growth, stress responses, and virulence. The potential of HDAC inhibitors, currently under development for cancer therapy, as novel alternative antifungal agents against IA is discussed.

  15. The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech

    2017-01-01

    While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944

  16. Engineering Recombinant Protein Sensors for Quantifying Histone Acetylation.

    Science.gov (United States)

    Sanchez, Oscar F; Mendonca, Agnes; Carneiro, Ana D; Yuan, Chongli

    2017-03-24

    H3K14ac (acetylation of lysine 14 of histone H3) is one of the most important epigentic modifications. Aberrant changes in H3K14ac have been associated with various diseases, including cancers and neurological disorders. Tools that enable detection and quantification of H3K14ac levels in cell extracts and in situ are thus of critical importance to reveal its role in various biological processes. Current detection techniques of specific histone modifications, however, are constrained by tedious sample pretreatments, lack of quantitative accuracy, and reliance on high quality antibodies. To address this issue, we engineered recombinant sensors that are suitable for probing histone acetylation levels using various biological samples. The protein sensor contains recongition domain(s) with sequences derived from the bromodomain of human polybromo-1 (PB1), a natural H3K14ac reader domain. Various sensor designs were tested using nuclear extracts and live cells. The sensor containing dimeric repeats of bromodomain was found most effective in quantifying H3K14ac level in both in vitro and in situ assays. The sensor has a linear detection range of 0.5-50 nM when mixed with nuclear extracts. The sensor colocalizes with H3K14ac antibodies in situ when transfected into human embryonic kidney 293T (HEK293T) cells and is thus capable of providing spatial details of histone modification within the nucleus. Corrected nuclear fluorescence intensity was used to quantify the modification level in situ and found to correlate well with our in vitro assays. Our sensor offers a novel tool to characterize the histone modification level using nuclear extracts and probe histone modification change in live cells.

  17. Biochemical systems approaches for the analysis of histone modification readout.

    Science.gov (United States)

    Soldi, Monica; Bremang, Michael; Bonaldi, Tiziana

    2014-08-01

    Chromatin is the macromolecular nucleoprotein complex that governs the organization of genetic material in the nucleus of eukaryotic cells. In chromatin, DNA is packed with histone proteins into nucleosomes. Core histones are prototypes of hyper-modified proteins, being decorated by a large number of site-specific reversible and irreversible post-translational modifications (PTMs), which contribute to the maintenance and modulation of chromatin plasticity, gene activation, and a variety of other biological processes and disease states. The observations of the variety, frequency and co-occurrence of histone modifications in distinct patterns at specific genomic loci have led to the idea that hPTMs can create a molecular barcode, read by effector proteins that translate it into a specific transcriptional state, or process, on the underlying DNA. However, despite the fact that this histone-code hypothesis was proposed more than 10 years ago, the molecular details of its working mechanisms are only partially characterized. In particular, two questions deserve specific investigation: how the different modifications associate and synergize into patterns and how these PTM configurations are read and translated by multi-protein complexes into a specific functional outcome on the genome. Mass spectrometry (MS) has emerged as a versatile tool to investigate chromatin biology, useful for both identifying and validating hPTMs, and to dissect the molecular determinants of histone modification readout systems. We review here the MS techniques and the proteomics methods that have been developed to address these fundamental questions in epigenetics research, emphasizing approaches based on the proteomic dissection of distinct native chromatin regions, with a critical evaluation of their present challenges and future potential. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Dewatering Behaviour of Fine Oil Sands Tailings : An Experimental Study

    NARCIS (Netherlands)

    Yao, Y.

    2016-01-01

    Oil sands tailings are a warm aqueous suspension of sand, silt, clay, residual bitumen and naphtha. The tailings are hydraulically transported and stored in tailing ponds where they segregate, with the sand settling from suspension forming beaches and the remaining tailings flowing to the middle of

  19. DNA methylation pathways and their crosstalk with histone methylation

    Science.gov (United States)

    Du, Jiamu; Johnson, Lianna M.; Jacobsen, Steven E.; Patel, Dinshaw J.

    2015-01-01

    Methylation of DNA and of histone 3 at Lys 9 (H3K9) are highly correlated with gene silencing in eukaryotes from fungi to humans. Both of these epigenetic marks need to be established at specific regions of the genome and then maintained at these sites through cell division. Protein structural domains that specifically recognize methylated DNA and methylated histones are key for targeting enzymes that catalyse these marks to appropriate genome sites. Genetic, genomic, structural and biochemical data reveal connections between these two epigenetic marks, and these domains mediate much of the crosstalk. PMID:26296162

  20. Mechanisms of transcriptional repression by histone lysine methylation

    DEFF Research Database (Denmark)

    Hublitz, Philip; Albert, Mareike; Peters, Antoine H F M

    2009-01-01

    . In this report, we review the recent literature to deduce mechanisms underlying Polycomb and H3K9 methylation mediated repression, and describe the functional interplay with activating H3K4 methylation. We summarize recent data that indicate a close relationship between GC density of promoter sequences......, transcription factor binding and the antagonizing activities of distinct epigenetic regulators such as histone methyltransferases (HMTs) and histone demethylases (HDMs). Subsequently, we compare chromatin signatures associated with different types of transcriptional outcomes from stable repression to highly...... dynamic regulated genes, strongly suggesting that the interplay of different epigenetic pathways is essential in defining specific types of heritable chromatin and associated transcriptional states....

  1. Two distinct modes for propagation of histone PTMs across the cell cycle

    DEFF Research Database (Denmark)

    Alabert, Constance; Barth, Teresa K; Reverón-Gómez, Nazaret

    2015-01-01

    to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and trimethylation marks are diluted twofold upon DNA replication, as a consequence...... of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment...... of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle....

  2. Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network

    NARCIS (Netherlands)

    Kanski, Regina; Sneeboer, Marjolein A M; van Bodegraven, Emma J; Sluijs, Jacqueline A; Kropff, Wietske; Vermunt, Marit W.; Creyghton, Menno P; De Filippis, Lidia; Vescovi, Angelo; Aronica, Eleonora; van Tijn, P.; van Strien, Miriam E; Hol, Elly M

    2014-01-01

    Glial fibrillary acidic protein (GFAP) is the main intermediate filament in astrocytes and is regulated by epigenetic mechanisms during development. We demonstrate that histone acetylation also controls GFAP expression in mature astrocytes. Inhibition of histone deacetylases (HDACs) with

  3. Substrate Specificity Profiling of Histone-Modifying Enzymes by Peptide Microarray.

    Science.gov (United States)

    Cornett, E M; Dickson, B M; Vaughan, R M; Krishnan, S; Trievel, R C; Strahl, B D; Rothbart, S B

    2016-01-01

    The dynamic addition and removal of covalent posttranslational modifications (PTMs) on histone proteins serves as a major mechanism regulating chromatin-templated biological processes in eukaryotic genomes. Histone PTMs and their combinations function by directly altering the physical structure of chromatin and as rheostats for effector protein interactions. In this chapter, we detail microarray-based methods for analyzing the substrate specificity of lysine methyltransferase and demethylase enzymes on immobilized synthetic histone peptides. Consistent with the "histone code" hypothesis, we reveal a strong influence of adjacent and, surprisingly, distant histone PTMs on the ability of histone-modifying enzymes to methylate or demethylate their substrates. This platform will greatly facilitate future investigations into histone substrate specificity and mechanisms of PTM signaling that regulate the catalytic properties of histone-modifying enzymes. © 2016 Elsevier Inc. All rights reserved.

  4. Volume reduction of Clark hot water extraction fine tailings

    Energy Technology Data Exchange (ETDEWEB)

    Sheeran, E. D. [ed.

    1995-06-01

    The principal focus of this volume is the reduction or elimination of the accumulation of fine tailings produced by the Clark Hot Water Extraction (CHWE) process, the process which is currently employed by commercial oil sands extraction operations in Alberta. Several opportunities in the process where reduction of fine tailings accumulation might be accomplished through either chemical or mechanical modifications, have been examined. Among these are: (1) selective mining, (2) alternate extraction processes, (3) prevention of segregation of coarse and fine tailings, (4) recombination of extraction tailings and fine tailings, (5) extraction of water from mature tailings, and (6) stabilization of mature fine tailings. 77 refs., tabs., figs.

  5. Role of chromatin structure modulation by the histone deacetylase inhibitor trichostatin A on the radio-sensitivity of ataxia telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Meschini, Roberta, E-mail: meschini@unitus.it; Morucci, Elisa; Berni, Andrea; Lopez-Martinez, Wilner; Palitti, Fabrizio

    2015-07-15

    Highlights: • Role of chromatin compaction on chromosomal instability. • Reduced radiation-induced clastogenicity in Ataxia telangiectasia cell lines. • Histone tails hyperacetylation reduces heterochromatin content favouring DSBs repair. - Abstract: At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionising radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post

  6. EPC1/TIP60-mediated histone acetylation facilitates spermiogenesis in mice

    DEFF Research Database (Denmark)

    Dong, Yixin; Isono, Kyo Ichi; Ohbo, Kazuyuki

    2017-01-01

    Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation- mediated histone replacement remains poorly understood. Here...... spermatid development. Taking these observations together, we reveal an essential role of the NuA4 complexes for histone hyperacetylation and subsequent compaction of the spermatid genome....

  7. Quantitative analysis of histone modifications: formaldehyde is a source of pathological n(6-formyllysine that is refractory to histone deacetylases.

    Directory of Open Access Journals (Sweden)

    Bahar Edrissi

    Full Text Available Aberrant protein modifications play an important role in the pathophysiology of many human diseases, in terms of both dysfunction of physiological modifications and the formation of pathological modifications by reaction of proteins with endogenous electrophiles. Recent studies have identified a chemical homolog of lysine acetylation, N(6-formyllysine, as an abundant modification of histone and chromatin proteins, one possible source of which is the reaction of lysine with 3'-formylphosphate residues from DNA oxidation. Using a new liquid chromatography-coupled to tandem mass spectrometry method to quantify all N(6-methyl-, -acetyl- and -formyl-lysine modifications, we now report that endogenous formaldehyde is a major source of N(6-formyllysine and that this adduct is widespread among cellular proteins in all compartments. N(6-formyllysine was evenly distributed among different classes of histone proteins from human TK6 cells at 1-4 modifications per 10(4 lysines, which contrasted strongly with lysine acetylation and mono-, di-, and tri-methylation levels of 1.5-380, 5-870, 0-1400, and 0-390 per 10(4 lysines, respectively. While isotope labeling studies revealed that lysine demethylation is not a source of N(6-formyllysine in histones, formaldehyde exposure was observed to cause a dose-dependent increase in N(6-formyllysine, with use of [(13C,(2H2]-formaldehyde revealing unchanged levels of adducts derived from endogenous sources. Inhibitors of class I and class II histone deacetylases did not affect the levels of N(6-formyllysine in TK6 cells, and the class III histone deacetylase, SIRT1, had minimal activity (<10% with a peptide substrate containing the formyl adduct. These data suggest that N(6-formyllysine is refractory to removal by histone deacetylases, which supports the idea that this abundant protein modification could interfere with normal regulation of gene expression if it arises at conserved sites of physiological protein secondary

  8. 75 FR 62445 - Otter Tail Valley Railroad Company, Inc.-Abandonment Exemption-in Otter Tail County, MN

    Science.gov (United States)

    2010-10-08

    ... (Sub-No. 4X)] Otter Tail Valley Railroad Company, Inc.-Abandonment Exemption-- in Otter Tail County, MN Otter Tail Valley Railroad Company, Inc. (OTVR) filed a verified notice of exemption under 49 CFR part... milepost 48.422 near Fergus Falls, and milepost 47.60 near Hoot Lake, in Otter Tail County, Minn.\\1\\ The...

  9. Electro-remediation of copper mine tailings. Comparing copper removal efficiencies for two tailings of different age

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Lamas, Victor; Gutierrez, Claudia

    2013-01-01

    This work compares and evaluates the copper removal efficiency when applying electric fields to two mine tailings originating from the same mine but of different age. Eight experiments were carried out - four on tailings deposited more than 20 years ago (old tailings) and four on tailings deposit...

  10. Low charge state heavy ion production with sub-nanosecond laser.

    Science.gov (United States)

    Kanesue, T; Kumaki, M; Ikeda, S; Okamura, M

    2016-02-01

    We have investigated laser ablation plasma of various species using nanosecond and sub-nanosecond lasers for both high and low charge state ion productions. We found that with sub-nanosecond laser, the generated plasma has a long tail which has low charge state ions determined by an electrostatic ion analyzer even under the laser irradiation condition for highly charged ion production. This can be caused by insufficient laser absorption in plasma plume. This property might be suitable for low charge state ion production. We used a nanosecond laser and a sub-nanosecond laser for low charge state ion production to investigate the difference of generated plasma using the Zirconium target.

  11. Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant.

    Science.gov (United States)

    Earnshaw, W C; Allshire, R C; Black, B E; Bloom, K; Brinkley, B R; Brown, W; Cheeseman, I M; Choo, K H A; Copenhaver, G P; Deluca, J G; Desai, A; Diekmann, S; Erhardt, S; Fitzgerald-Hayes, M; Foltz, D; Fukagawa, T; Gassmann, R; Gerlich, D W; Glover, D M; Gorbsky, G J; Harrison, S C; Heun, P; Hirota, T; Jansen, L E T; Karpen, G; Kops, G J P L; Lampson, M A; Lens, S M; Losada, A; Luger, K; Maiato, H; Maddox, P S; Margolis, R L; Masumoto, H; McAinsh, A D; Mellone, B G; Meraldi, P; Musacchio, A; Oegema, K; O'Neill, R J; Salmon, E D; Scott, K C; Straight, A F; Stukenberg, P T; Sullivan, B A; Sullivan, K F; Sunkel, C E; Swedlow, J R; Walczak, C E; Warburton, P E; Westermann, S; Willard, H F; Wordeman, L; Yanagida, M; Yen, T J; Yoda, K; Cleveland, D W

    2013-04-01

    The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.

  12. Tail Asymptotics for the Sum of two Heavy-tailed Dependent Risks

    DEFF Research Database (Denmark)

    Albrecher, H.; Asmussen, Søren

    Let X1,X2 denote positive exchangable heavy-tailed random variables with continuous marginal distribution function F. The asymptotic behavior of the tail of X1 + X2 is studied in a general copula framework and some bounds and extremal properties are provided. For more specific assumptions on F...

  13. Attitudes of Dutch Pig Farmers Towards Tail Biting and Tail Docking

    NARCIS (Netherlands)

    Bracke, M.B.M.; Lauwere, de C.C.; Wind, S.M.M.; Zonderland, J.J.

    2013-01-01

    The Dutch policy objective of a fully sustainable livestock sector without mutilations by 2023 is not compatible with the routine practice of tail docking to minimize the risk of tail biting. To examine farmer attitudes towards docking, a telephone survey was conducted among 487 conventional and 33

  14. Effects of tail docking and docking length on neuroanatomical changes in healed tail tips of pigs.

    Science.gov (United States)

    Herskin, M S; Thodberg, K; Jensen, H E

    2015-04-01

    In pig production, piglets are tail docked at birth in order to prevent tail biting later in life. In order to examine the effects of tail docking and docking length on the formation of neuromas, we used 65 pigs and the following four treatments: intact tails (n=18); leaving 75% (n=17); leaving 50% (n=19); or leaving 25% (n=11) of the tail length on the pigs. The piglets were docked between day 2 and 4 after birth using a gas-heated apparatus, and were kept under conventional conditions until slaughter at 22 weeks of age, where tails were removed and examined macroscopically and histologically. The tail lengths and diameters differed at slaughter (lengths: 30.6±0.6; 24.9±0.4; 19.8±0.6; 8.7±0.6 cm; Ptail diameter: 0.5±0.03; 0.8±0.02; 1.0±0.03; 1.4±0.04 cm; Ptails with neuromas (64 v. 0%; Ptail (1.0±0.2 v. 0; Ptail docking piglets using hot-iron cautery causes formation of neuromas in the outermost part of the tail tip. The presence of neuromas might lead to altered nociceptive thresholds, which need to be confirmed in future studies.

  15. Generalized processor sharing with light-tailed and heavy-tailed input

    NARCIS (Netherlands)

    Borst, Sem; Mandjes, M.R.H.; van Uitert, Miranda

    2003-01-01

    We consider a queue fed by a mixture of light-tailed and heavy-tailed traffic. The two traffic flows are served in accordance with the generalized processor sharing (GPS) discipline. GPS-based scheduling algorithms, such as weighted fair queueing, have emerged as an important mechanism for achieving

  16. Single-Tailed Lipidoids Enhance the Transfection Activity of Their Double-Tailed Counterparts.

    Science.gov (United States)

    Wu, Yihang; Li, Linxian; Chen, Qing; Su, Yi; Levkin, Pavel A; Davidson, Gary

    2016-01-11

    Cationic lipid-like molecules (lipidoids) are widely used for in vitro and in vivo gene delivery. Nearly all lipidoids developed to date employ double-tail or multiple-tail structures for transfection. Single-tail lipidoids are seldom considered for transfection as they have low efficiency in gene delivery. So far, there is no detailed study on the contribution to transfection efficiency of single-tail lipidoids when combined with standard double-tail lipidoids. Here, we use combinatorial chemistry to synthesize 17 double-tail and 17 single-tail lipidoids using thiol-yne and thiol-ene click chemistry, respectively. HEK 293T cells were used to analyze transfection efficiency by fluorescence microscopy and calculated based on the percentage of cells transfected. The size and zeta potential of liposomes and lipoplexes were characterized by dynamic light scattering (DLS). Intracellular DNA delivery and trafficking was further examined using confocal microscopy. Our study shows that combining single with double-tail lipidoids increases uptake of lipoplexes, as well as cellular transfection efficiency.

  17. Patterns and Mechanisms of Ancestral Histone Protein Inheritance in Budding Yeast

    Science.gov (United States)

    van Welsem, Tibor; Friedman, Nir; Rando, Oliver J.; van Leeuwen, Fred

    2011-01-01

    Replicating chromatin involves disruption of histone-DNA contacts and subsequent reassembly of maternal histones on the new daughter genomes. In bulk, maternal histones are randomly segregated to the two daughters, but little is known about the fine details of this process: do maternal histones re-assemble at preferred locations or close to their original loci? Here, we use a recently developed method for swapping epitope tags to measure the disposition of ancestral histone H3 across the yeast genome over six generations. We find that ancestral H3 is preferentially retained at the 5′ ends of most genes, with strongest retention at long, poorly transcribed genes. We recapitulate these observations with a quantitative model in which the majority of maternal histones are reincorporated within 400 bp of their pre-replication locus during replication, with replication-independent replacement and transcription-related retrograde nucleosome movement shaping the resulting distributions of ancestral histones. We find a key role for Topoisomerase I in retrograde histone movement during transcription, and we find that loss of Chromatin Assembly Factor-1 affects replication-independent turnover. Together, these results show that specific loci are enriched for histone proteins first synthesized several generations beforehand, and that maternal histones re-associate close to their original locations on daughter genomes after replication. Our findings further suggest that accumulation of ancestral histones could play a role in shaping histone modification patterns. PMID:21666805

  18. Characterization of lysine 56 of histone H3 as an acetylation site in Saccharomyces cerevisiae.

    NARCIS (Netherlands)

    Ozdemir, A.; Spicuglia, S.; Lasonder, E.; Vermeulen, M.; Campsteijn, C.G.; Stunnenberg, H.G.; Logie, C.

    2005-01-01

    Post-translational histone modifications abound and regulate multiple nuclear processes. Most modifications are targeted to the amino-terminal domains of histones. Here we report the identification and characterization of acetylation of lysine 56 within the core domain of histone H3. In the crystal

  19. Autoantibodies against citrullinated histone H3 in rheumatoid arthritis and periodontitis patients

    NARCIS (Netherlands)

    Janssen, Koen M. J.; de Smit, Menke J.; Withaar, Coenraad; Brouwer, Elisabeth; van Winkelhoff, Arie J.; Vissink, Arjan; Westra, Johanna

    Aim: To determine the presence of citrullinated histones in inflamed periodontal tissue and to determine the presence of anti-citrullinated histone autoantibodies in sera from patients with rheumatoid arthritis (RA) and periodontitis (PD) patients. Methods: The presence of citrullinated histone H3,

  20. Histone deacetylase inhibitors induced differentiation and accelerated mineralization of pulp-derived cells.

    LENUS (Irish Health Repository)

    Duncan, Henry F

    2012-03-01

    Histone deacetylase inhibitors (HDACis) alter the homeostatic balance between 2 groups of cellular enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs), increasing transcription and influencing cell behavior. This study investigated the potential of 2 HDACis, valproic acid (VPA) and trichostatin A (TSA), to promote reparative processes in pulp cells as assayed by viability, cell cycle, and mineralization analyses.

  1. Variations of Histone Modification Patterns: Contributions of Inter-plant Variability and Technical Factors

    OpenAIRE

    Sylva Brabencová; Sylva Brabencová; Ivana Ihnatová; David Potěšil; Miloslava Fojtová; Miloslava Fojtová; Jiří Fajkus; Jiří Fajkus; Zbyněk Zdráhal; Zbyněk Zdráhal; Gabriela Lochmanová

    2017-01-01

    Inter-individual variability of conspecific plants is governed by differences in their genetically determined growth and development traits, environmental conditions, and adaptive responses under epigenetic control involving histone post-translational modifications. The apparent variability in histone modifications among plants might be increased by technical variation introduced in sample processing during epigenetic analyses. Thus, to detect true variations in epigenetic histone patterns as...

  2. Dual modified antiphospho (Ser10)-acetyl (Lys14)-histone H3 ...

    Indian Academy of Sciences (India)

    SANTOSH KUMAR SHARMA

    histone may serve as an additional cytogenetic landmark to identify pericentromeric chromatin during mitosis in plants. The plausible role of histone cross talk and future perspectives of combinatorial histone modification marks in plant cytogenetics with special reference to chromatin dynamics have been discussed.

  3. The histone deacetylase inhibitor trichostatin A reduces nickel-induced gene silencing in yeast and mammalian cells.

    Science.gov (United States)

    Sutherland, J E; Peng, W; Zhang, Q; Costa, M

    2001-08-08

    We have previously reported that nickel (Ni)-silenced expression of the URA3 gene in yeast (Saccharomyces cerevisiae) and gpt transgene in G12 Chinese hamster cells. In both cases, close proximity to a heterochromatic region was required for gene silencing. Yeast exposed to Ni exhibited reduced acetylation of the lysine residues in the N-terminal tail of histone H4. Ni-induced silencing of the gpt gene in mammalian cells involved hypermethylation of promoter region DNA. Yeast do not employ DNA methylation to silence gene expression. To determine if histone deacetylation participates in Ni-induced silencing of the URA3 and gpt genes, we exposed yeast and G12 hamster cells to the histone deacetylase inhibitor trichostatin A (TSA) prior to and concurrently with Ni. Treatment of yeast cells with 0.2-0.6mM NiCl(2) resulted in reduced expression of the URA3 gene as assessed by increased resistance to 1g/l 5-fluorotic acid (5-FOA). This effect was lessened when yeast were pre-treated with 50 microg TSA/ml. Similarly, treatment of G12 cells with 5 ng/ml TSA during and after exposure to 0.3 microg Ni(3)S(2)/cm(2) reduced silencing of the gpt gene as gauged by resistance to 10 microg/ml 6-thioguanine (6-TG). The ability of TSA alone and in combination with the DNA-demethylating agent (5-AzaC) to reactivate the gpt gene in Ni-silenced variants was also assessed. Although treatment with 100 ng/ml TSA for 48 h was partially effective in reactivating the gpt gene, treatment with 5 microM 5-AzaC was more efficacious. The greatest gpt gene reversion frequencies were observed following a sequential 5-AzaC/TSA treatment. Taken all together, our data from mammalian cells suggests that both DNA methylation and histone deacetylation participate in Ni-induced silencing of the gpt gene with DNA hypermethylation playing the more dominant role in maintaining the silenced state.

  4. Histone code and long non-coding RNAs (lncRNAs) aberrations in lung cancer: implications in the therapy response.

    Science.gov (United States)

    Herrera-Solorio, Abril Marcela; Armas-López, Leonel; Arrieta, Oscar; Zúñiga, Joaquín; Piña-Sánchez, Patricia; Ávila-Moreno, Federico

    2017-01-01

    Respiratory diseases hold several genome, epigenome, and transcriptional aberrations as a cause of the accumulated damage promoted by, among others, environmental risk factors. Such aberrations can also come about as an adaptive response when faced with therapeutic oncological drugs. In epigenetic terms, aberrations in DNA methylation patterns, histone code marks balance, and/or chromatin-remodeling complexes recruitment, among Polycomb Repressive Complex-2 (PRC2) versus Trithorax (TRX) Activator Complex, have been proposed to be affected by several previously characterized functional long non-coding RNAs (lncRNAs). Such molecules are involved in modulating and/or controlling lung cancer epigenome and genome expression, as well as in malignancy and clinical progression in lung cancer. Several recent reports have described diverse epigenetic modifications in lung cancer cells and solid tumors, among others genomic DNA methylation and post-translational modifications (PTMs) on histone tails, as well as lncRNAs patterns and levels of expression. However, few systematic approaches have attempted to demonstrate a biological function and clinical association, aiming to improve therapeutic decisions in basic research and lung clinical oncology. A widely used example is the lncRNA HOTAIR and its functional histone mark H3K27me3, which is directly associated to the PRC2; however, few systematic pieces of solid evidence have been experimentally performed, conducted and/or validated to predict lung oncological therapeutic efficacy. Recent evidence suggests that chromatin-remodeling complexes accompanied by lncRNAs profiles are involved in several comprehensive lung carcinoma clinical parameters, including histopathology progression, prognosis, and/or responsiveness to unique or combined oncological therapies. The present manuscript offers a systematic revision of the current knowledge about the major epigenetic aberrations represented by changes in histone PTMs and lnc

  5. Cognition in ring-tailed lemurs.

    Science.gov (United States)

    Kittler, Klara; Schnoell, Anna Viktoria; Fichtel, Claudia

    2015-01-01

    In order to better understand the evolution of cognitive abilities in primates, information on cognitive traits of the most basal living primates can provide important comparative baseline data. Compared to haplorhine primates, lemurs have relatively smaller brains and reduced abilities to solve problems in the technical and social domain. However, recent studies have suggested that some cognitive abilities of lemurs are qualitatively equal to those of haplorhines. Here, we review studies investigating cognitive abilities in the technical and social domain of ring-tailed lemur cognition. In the physical domain, ring-tailed lemurs exhibit similar qualitative cognitive skills as other lemurs but also haplorhine primates. In the social domain, ring-tailed lemurs appear to be more skilled in visual perspective taking than other lemurs. Compared to other lemurs, they also have highly elaborated communicative skills. Moreover, within-group coalitions have been observed in female ring-tailed lemurs during rare events of female evictions but not in other lemur species. However, in several other aspects of social cognition, such as reconciliation and social learning, ring-tailed lemurs' cognitive abilities are equal to those of other lemurs. Thus, additional systematic comparative studies in physical and social cognition are required for a more comprehensive understanding of the processes of cognitive evolution among primates. © 2015 S. Karger AG, Basel.

  6. Mechanistic stochastic model of histone modification pattern formation

    NARCIS (Netherlands)

    Anink-Groenen, L.C.M.; Maarleveld, T.R.; Verschure, P.J.; Bruggeman, F.J.

    2014-01-01

    BACKGROUND: The activity of a single gene is influenced by the composition of the chromatin in which it is embedded. Nucleosome turnover, conformational dynamics, and covalent histone modifications each induce changes in the structure of chromatin and its affinity for regulatory proteins. The

  7. Ontogenetic Survey of Histone Modifications in an Annelid

    Directory of Open Access Journals (Sweden)

    Glenys Gibson

    2012-01-01

    Full Text Available Histone modifications are widely recognized for their fundamental importance in regulating gene expression in embryonic development in a wide range of eukaryotes, but they have received relatively little attention in the development of marine invertebrates. We surveyed histone modifications throughout the development of a marine annelid, Polydora cornuta, to determine if modifications could be detected immunohistochemically and if there were characteristic changes in modifications throughout ontogeny (surveyed at representative stages from oocyte to adult. We found a common time of onset for three histone modifications in early cleavage (H3K14ac, H3K9me, and H3K4me2, some differences in the distribution of modifications among germ layers, differences in epifluorescence intensity in specific cell lineages suggesting that hyperacetylation (H3K14ac and hypermethylation (H3K9me occur during differentiation, and an overall decrease in the distribution of modifications from larvae to adults. Although preliminary, these results suggest that histone modifications are involved in activating early development and differentiation in a marine invertebrate.

  8. Distribution pattern of histone H3 phosphorylation at serine 10 ...

    Indian Academy of Sciences (India)

    2013-08-06

    Aug 6, 2013 ... in chromosome distribution of H3S10ph when mitosis and meiosis were compared. ... [Paula C. M. P., Techio V. H., Sobrinho F. S. and Freitas A. S. 2013 Distribution pattern of histone H3 phosphorylation at serine 10 during mitosis and meiosis in ... RDWebster], since current knowledge about specific roles ...

  9. Differential patterns of histone acetylation in inflammatory bowel diseases

    Directory of Open Access Journals (Sweden)

    Adcock Ian M

    2011-01-01

    Full Text Available Abstract Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy samples from patients with Crohn's disease (CD to study the expression of acetylated histones (H 3 and 4 in inflamed mucosa. Acetylation of histone H4 was significantly elevated in the inflamed mucosa in the trinitrobenzene sulfonic acid model of colitis particularly on lysine residues (K 8 and 12 in contrast to non-inflamed tissue. In addition, acetylated H4 was localised to inflamed tissue and to Peyer's patches (PP in dextran sulfate sodium (DSS-treated rat models. Within the PP, H3 acetylation was detected in the mantle zone whereas H4 acetylation was seen in both the periphery and the germinal centre. Finally, acetylation of H4 was significantly upregulated in inflamed biopsies and PP from patients with CD. Enhanced acetylation of H4K5 and K16 was seen in the PP. These results demonstrate that histone acetylation is associated with inflammation and may provide a novel therapeutic target for mucosal inflammation.

  10. Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

    DEFF Research Database (Denmark)

    Maolanon, Alex; Kristensen, Helle; Leman, Luke

    2017-01-01

    Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration (FDA) in the US, and several are currently in clinical trials. However, none of these compounds...

  11. Effect of histone deacetylase inhibitor, trichostatin A, on cartilage ...

    African Journals Online (AJOL)

    Purpose: To evaluate the effect of histone deacetylase (HDAC) inhibitor, trichostatin A (TCA), on cartilage regeneration in a rabbit perichondrial graft model. Methods: Perichondrial grafts (20 × 20 mm2) were derived from the ears of New Zealand rabbits and transplanted onto the paravertebral muscle of the face of each ...

  12. Properly reading the histone code by MS-based proteomics.

    Science.gov (United States)

    Sidoli, Simone; Garcia, Benjamin A

    2015-09-01

    Histone proteins are essential elements for DNA packaging. Their PTMs contribute in modeling chromatin structure and recruiting enzymes involved in gene regulation, DNA repair, and chromosome condensation. This fundamental aspect, together with the fact that histone PTMs can be epigenetically inherited through cell generations, enlightens their importance in chromatin biology, and the consequent necessity of having biochemical techniques for their characterization. Nanoflow LC coupled to MS (nanoLC-MS) is the strategy of choice for protein PTM accurate quantification. However, histones require adjustments to the digestion protocol such as lysine derivatization to obtain suitable peptides for the analysis. nanoLC-MS has numerous advantages, spanning from high confidence identification to possibility of high throughput analyses, but the peculiarity of the histone preparation protocol requires continuous monitoring with the most modern available technologies to question its reliability. The work of Meert et al. (Proteomics 2015, 15, 2966-2971) establishes which protocols lead to either incomplete derivatization or derivatization of undesired amino acid residues using a combination of high resolution MS and bioinformatics tools for the alignment and the characterization of nanoLC-MS runs. As well, they identify a number of side reactions that could be potentially misinterpreted as biological PTMs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Experimental Approaches Toward Histone Acetyltransferase Inhibitors as Therapeutics

    NARCIS (Netherlands)

    Dekker, Frank; Tollefsbol, Trygve

    2016-01-01

    This chapter comprises the most recent developments with respect to the role of human histone acetyltransferases (HATs) in diseases and the potential therapeutic applications of HAT inhibitors. HATs form a diverse group of mainly nuclear enzymes that play an important role in the acetylation of

  14. resistance-induced expression and histone modifications of WRKY ...

    Indian Academy of Sciences (India)

    FLD codes for a homologue of human-lysine-specific histone demethylase. Here we show that FLD function is required for priming (SAR induced elevated expression during challenge inoculation) of WRKY29 and WRKY6 genes. FLD also differentially influences basal and SAR-induced expression of WRKY38, WRKY65 ...

  15. Innovative Strategies for Selective Inhibition of Histone Deacetylases

    DEFF Research Database (Denmark)

    Maolanon, Alex Ramalak; Madsen, Andreas Stahl; Olsen, Christian Adam

    2016-01-01

    Histone deacetylases (HDAC) are a family of closely related enzymes involved in epigenetic and posttranscriptional regulation of numerous genes and proteins. Their deregulation is associated with a number of diseases, and a handful of HDAC inhibitors have been approved for cancer treatment. None ...

  16. resistance-induced expression and histone modifications of WRKY ...

    Indian Academy of Sciences (India)

    2014-01-27

    Jan 27, 2014 ... Ross AF 1961 Systemic acquired resistance induced by localized virus infections in plants. Virology 14 340–358. Saleh A, Alvarez-Venegas R and Avramova Z 2008 An efficient chro- matin immunoprecipitation (ChIP) protocol for studying histone mod- ifications in Arabidopsis plants. Nat. Protocols 3 1018– ...

  17. Cell shape regulates global histone acetylation in human mammaryepithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Le Beyec, Johanne; Xu, Ren; Lee, Sun-Young; Nelson, Celeste M.; Rizki, Aylin; Alcaraz, Jordi; Bissell, Mina J.

    2007-02-28

    Extracellular matrix (ECM) regulates cell morphology and gene expression in vivo; these relationships are maintained in three-dimensional (3D) cultures of mammary epithelial cells. In the presence of laminin-rich ECM (lrECM), mammary epithelial cells round up and undergo global histone deacetylation, a process critical for their functional differentiation. However, it remains unclear whether lrECM-dependent cell rounding and global histone deacetylation are indeed part of a common physical-biochemical pathway. Using 3D cultures as well as nonadhesive and micropatterned substrata, here we showed that the cell 'rounding' caused by lrECM was sufficient to induce deacetylation of histones H3 and H4 in the absence of biochemical cues. Microarray and confocal analysis demonstrated that this deacetylation in 3D culture is associated with a global increase in chromatin condensation and a reduction in gene expression. Whereas cells cultured on plastic substrata formed prominent stress fibers, cells grown in 3D lrECM or on micropatterns lacked these structures. Disruption of the actin cytoskeleton with cytochalasin D phenocopied the lrECM-induced cell rounding and histone deacetylation. These results reveal a novel link between ECM-controlled cell shape and chromatin structure, and suggest that this link is mediated by changes in the actin cytoskeleton.

  18. Targeting Histone Acetylation: Readers and Writers in Leukemia and Cancer.

    Science.gov (United States)

    Benton, Christopher B; Fiskus, Warren; Bhalla, Kapil N

    Chromatin packaging of DNA provides a framework for transcriptional regulation. Modifications to DNA and histone proteins in nucleosomes lead to conformational changes, alterations in the recruitment of transcriptional complexes, and ultimately modulation of gene expression. We provide a focused review of control mechanisms that help modulate the activation and deactivation of gene transcription specifically through histone acetylation writers and readers in cancer. The chemistry of these modifications is subject to clinically actionable targeting, including state-of-the-art strategies to inhibit basic oncogenic mechanisms related to histone acetylation. Although discussed in the context of acute leukemia, the concepts of acetylation writers and readers are not cell-type-specific and are generalizable to other cancers. We review the challenges and resistance mechanisms encountered to date in the development of such therapeutics and postulate how such challenges may be overcome. Because these fundamental cellular mechanisms are dysregulated in cancer biology, continued research and in-depth understanding of histone acetylation reading and writing are desired to further define optimal therapeutic strategies to affect gene activity to target cancer effectively.

  19. Undetectable histone O-GlcNAcylation in mammalian cells

    Science.gov (United States)

    Gagnon, Jessica; Daou, Salima; Zamorano, Natalia; Iannantuono, Nicholas VG; Hammond-Martel, Ian; Mashtalir, Nazar; Bonneil, Eric; Wurtele, Hugo; Thibault, Pierre; Affar, El Bachir

    2015-01-01

    O-GlcNAcylation is a posttranslational modification catalyzed by the O-Linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and reversed by O-GlcNAcase (OGA). Numerous transcriptional regulators, including chromatin modifying enzymes, transcription factors, and co-factors, are targeted by O-GlcNAcylation, indicating that this modification is central for chromatin-associated processes. Recently, OGT-mediated O-GlcNAcylation was reported to be a novel histone modification, suggesting a potential role in directly coordinating chromatin structure and function. In contrast, using multiple biochemical approaches, we report here that histone O-GlcNAcylation is undetectable in mammalian cells. Conversely, O-GlcNAcylation of the transcription regulators Host Cell Factor-1 (HCF-1) and Ten-Eleven Translocation protein 2 (TET2) could be readily observed. Our study raises questions on the occurrence and abundance of O-GlcNAcylation as a histone modification in mammalian cells and reveals technical complications regarding the detection of genuine protein O-GlcNAcylation. Therefore, the identification of the specific contexts in which histone O-GlcNAcylation might occur is still to be established. PMID:26075789

  20. Implication of Posttranslational Histone Modifications in Nucleotide Excision Repair

    Directory of Open Access Journals (Sweden)

    Shisheng Li

    2012-09-01

    Full Text Available Histones are highly alkaline proteins that package and order the DNA into chromatin in eukaryotic cells. Nucleotide excision repair (NER is a conserved multistep reaction that removes a wide range of generally bulky and/or helix-distorting DNA lesions. Although the core biochemical mechanism of NER is relatively well known, how cells detect and repair lesions in diverse chromatin environments is still under intensive research. As with all DNA-related processes, the NER machinery must deal with the presence of organized chromatin and the physical obstacles it presents. A huge catalogue of posttranslational histone modifications has been documented. Although a comprehensive understanding of most of these modifications is still lacking, they are believed to be important regulatory elements for many biological processes, including DNA replication and repair, transcription and cell cycle control. Some of these modifications, including acetylation, methylation, phosphorylation and ubiquitination on the four core histones (H2A, H2B, H3 and H4 or the histone H2A variant H2AX, have been found to be implicated in different stages of the NER process. This review will summarize our recent understanding in this area.

  1. Post-Translational Modifications of Histones in Human Sperm

    Czech Academy of Sciences Publication Activity Database

    Krejčí, Jana; Stixová, Lenka; Legartová, Soňa; Kozubek, Stanislav; Lochmanová, G.; Zdráhal, Z.; Sehnalová, Petra; Dabravolski, S.; Hejatko, J.; Bártová, Eva

    2015-01-01

    Roč. 116, č. 10 (2015), s. 2195-2209 ISSN 0730-2312 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0068 Institutional support: RVO:68081707 Keywords : HUMAN SPERM * HISTONES * PROTAMINE P2 Subject RIV: BO - Biophysics Impact factor: 3.446, year: 2015

  2. Roles of the EZH2 histone methyltransferase in cancer epigenetics.

    Science.gov (United States)

    Simon, Jeffrey A; Lange, Carol A

    2008-12-01

    EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that targets lysine-27 of histone H3. This methylated H3-K27 chromatin mark is commonly associated with silencing of differentiation genes in organisms ranging from plants to flies to humans. Studies on human tumors show that EZH2 is frequently over-expressed in a wide variety of cancerous tissue types, including prostate and breast. Although the mechanistic contributions of EZH2 to cancer progression are not yet determined, functional links between EZH2-mediated histone methylation and DNA methylation suggest partnership with the gene silencing machinery implicated in tumor suppressor loss. Here we review the basic molecular biology of EZH2 and the findings that implicate EZH2 in different cancers. We also discuss EZH2 connections to other silencing enzymes, such as DNA methyltransferases and histone deacetylases, and we consider progress on deciphering mechanistic consequences of EZH2 overabundance and its potential roles in tumorigenesis. Finally, we review recent findings that link EZH2 roles in stem cells and cancer, and we consider prospects for integrating EZH2 blockade into strategies for developing epigenetic therapies.

  3. Relationship of histone acetylation to DNA topology and transcription.

    Science.gov (United States)

    Krajewski, W A; Luchnik, A N

    1991-12-01

    An autonomously replicating plasmid constructed from bovine papiloma virus (BPV) and pBR322 was stably maintained as a nuclear episome in a mouse cell culture. Addition to a cell culture of sodium butyrate (5 mM) induced an increase in plasmid DNA supercoiling of 3-5 turns, an increase in acetylation of cellular histones, and a decrease in plasmid transcription by 2- to 4-fold. After withdrawal of butyrate, DNA supercoiling began to fluctuate in a wave-like manner with an amplitude of up to 3 turns and a period of 3-4 h. These waves gradually faded by 24 h. The transcription of the plasmid and acetylation of cellular histones also oscillated with the same period. The wave-like alterations were not correlated with the cell cycle, for there was no resumption of DNA replication after butyrate withdrawal for at least 24 h. In vitro chemical acetylation of histones with acetyl adenylate also led to an increase in the superhelical density of plasmid DNA. The parallel changes in transcription, histone acetylation, and DNA supercoiling in vivo may indicate a functional innerconnection. Also, the observed in vivo variation in the level of DNA supercoiling directly indicates the possibility of its natural regulation in eukaryotic cells.

  4. Histone modification profiles characterize function-specific gene regulation.

    Science.gov (United States)

    Jung, Inkyung; Kim, Dongsup

    2012-10-07

    Chromatin modification is ubiquitous in gene regulation. Despite much effort, a systematic investigation is needed to understand whether each modification has a unique property depending on the function of its associated genes. Here, we show that consideration of function-specific histone modification profiles is important for accurate prediction of gene expression levels, and is maintained across cell types. The performance improvement is thought to originate from the association between modifications and gene expression levels for each biological function. The varying relationship between histone modifications and gene expression levels can be partly explained by considering function-specific PolII recruitment mechanisms, and is supported by more accurate predictions of PolII occupancies with function-specific modification profiles. We suggest that the function-specific binding of transcription factors and chromatin regulators may explain similar gene regulatory mechanisms, such as function-specific PolII recruitment, in each functional gene set. Our study demonstrates that each histone modification has a different characteristic according to the function of its associated genes; thus, different combinations of histone modification profiles characterize function-specific gene regulation. The current analysis is available on our web server (biodb.kaist.ac.kr/impohis). Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Fish 'tails' result from outgrowth and reduction of two separate ancestral tails.

    Science.gov (United States)

    Sallan, Lauren

    2016-12-05

    The symmetrical, flexible teleost fish 'tail' has been a prime example of recapitulation - evolutionary change (phylogeny) mirrored in development (ontogeny). Paleozoic ray-finned fishes (Actinopterygii), relatives of teleosts, exhibited ancestral scale-covered tails curved over their caudal fins. For over 150 years, this arrangement was thought to be retained in teleost larva and overgrown, mirroring an ancestral transformation series. New ontogenetic data for the 350-million-year-old teleost relative Aetheretmon overturns this long-held hypothesis. The ancestral state consists of two outgrowths with distinct organizers and growth trajectories; a lower median fin turned caudal fin, and an upper vertebrae-bearing tail, equivalent to that of tetrapods. These two tails appear at a shared developmental stage in Aetheretmon, teleosts and all living actinopterygians. Ontogeny does not recapitulate phylogeny; instead, differential outgrowth determines final morphology. In Aetheretmon and other Paleozoic fishes, the vertebrae-bearing tail continues to grow beyond the caudal fin. In teleosts, and some others, a stunted tail is eclipsed by the upward-expanding caudal fin, rendering a once ventral body margin as the terminus. The double tail likely reflects the ancestral state for bony fishes. Many tetrapods and non-teleost actinopterygians have undergone body elongation through tail outgrowth extension, by mechanisms likely shared with distal limbs. Teleosts have gone to the other extreme; losing tail outgrowth for functional reasons. Recognition of the tail as a limb-like outgrowth has important implications for the evolution of vertebrate form. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Offline signal tail-correction for the ALICE TPC

    Energy Technology Data Exchange (ETDEWEB)

    Arslandok, Mesut [Frankfurt Univ. (Germany). Inst. fuer Kernphysik; Collaboration: ALICE-Collaboration

    2013-07-01

    The ALICE Time Projection Chamber (TPC) is the main tracking and particle identification (PID) detector of ALICE at the CERN-LHC. It was designed for multiplicities of up to 20,000 primary and secondary charged particles emerging from a single central Pb-Pb collision. The PID in the TPC is calculated from the specific energy loss measurement (dE/dx), which is derived from the pulse height distribution of charged particle tracks measured along 159 read-out planes. The signals from the Multi Wire Proportional Chambers (MWPC) show a characteristic long undershoot after the signal, which is due to the long ion drift times in the MWPC amplification region. Such an ''ion tail'' may lead to a loss of signal amplitude for the following signals on the same readout pad. Eventually, this results in a deterioration of the dE/dx resolution, in particular in the high multiplicity environment of Pb-Pb collisions. In this study, an offline correction method is presented which is expected to improve the dE/dx resolution and thus the PID quality of TPC. The method will be applied to the Pb-Pb collision data set taken in 2010 and 2011. Details of the correction procedure and first results are presented.

  7. LADEE UVS Observations of Atoms and Dust in the Lunar Tail

    Science.gov (United States)

    Wooden, Diane H.; Colaprete, Anthony; Cook, Amanda M.; Shirley, Mark H.; Vargo, Kara E.; Elphic, Richard C.; Stubbs, Timothy J.; Glenar, David A.

    2014-01-01

    The Lunar Atmosphere and Dust Environment Explorer (LADEE) was a lunar orbiter launched in September 2013 that investigated the composition and temporal variation of the tenuous lunar exosphere and dust environment. A major goal of the mission was to characterize the dust exosphere prior to future lunar exploration activities, which may alter the lunar environment. The Ultraviolet/Visible Spectrometer (UVS) onboard LADEE addresses this goal, utilizing two sets of optics: a limbviewing telescope, and a solar-viewing telescope. We report on spectroscopic (approximately 280 - 820 nm) observations viewing down the lunar wake or along the 'lunar tail' from lunar orbit. Prior groundbased studies have observed the emission from neutral sodium atoms extended along the lunar tail, so often this region is referred to as the lunar sodium tail. UVS measurements were made on the dark side of the moon, with the UVS limb-viewing telescope pointed outward in the direction of the Moon's wake (almost anti-sun), during different lunar phases. These UVS observation activities sample a long column and allow the characterization of scattered light from dust and emission lines from atoms in the lunar tail. Observations in this UVS configuration show the largest excess of scattered blue light in our data set, indicative of the presence of small dust grains in the tail. Once lofted, nanoparticles may become charged and picked up by the solar wind, similar to the phenomena witnessed above Enceladus's northern hemisphere or by the STEREO/WAVES instrument while close to Earth's orbit. The UVS data show that small dust grains as well as atoms become entrained in the lunar tail.

  8. Design of tailing dam using red mud

    Science.gov (United States)

    Rout, Subrat; Sahoo, Tapaswini; Das, Sarat

    2013-06-01

    Red mud, waste industrial product from aluminum industries produced approximately 75 million tonnes every year with less than half of this is used. Storage of this unutilized red mud takes vast tracts of usable land and pollutes, land, air and water. Construction of high embankments, under passes, flyovers, tailing dams uses vast tract of natural resources (top soil) is also matter of concern as its takes thousands of years to form the natural soil. This paper discusses use of red mud for construction of tailing dam based on laboratory findings and finite element analysis. The geotechnical properties such as plasticity, compaction, permeability, shear strength characteristics and dispersion of red mud are presented. Stability and seepage analysis of tailing dams as per finite element analysis using the above geotechnical parameters is presented.

  9. Analysis of Myc-induced histone modifications on target chromatin.

    Directory of Open Access Journals (Sweden)

    Francesca Martinato

    Full Text Available The c-myc proto-oncogene is induced by mitogens and is a central regulator of cell growth and differentiation. The c-myc product, Myc, is a transcription factor that binds a multitude of genomic sites, estimated to be over 10-15% of all promoter regions. Target promoters generally pre-exist in an active or poised chromatin state that is further modified by Myc, contributing to fine transcriptional regulation (activation or repression of the afferent gene. Among other mechanisms, Myc recruits histone acetyl-transferases to target chromatin and locally promotes hyper-acetylation of multiple lysines on histones H3 and H4, although the identity and combination of the modified lysines is unknown. Whether Myc dynamically regulates other histone modifications (or marks at its binding sites also remains to be addressed. Here, we used quantitative chromatin immunoprecipitation (qChIP to profile a total of 24 lysine-acetylation and -methylation marks modulated by Myc at target promoters in a human B-cell line with a regulatable c-myc transgene. Myc binding promoted acetylation of multiple lysines, primarily of H3K9, H3K14, H3K18, H4K5 and H4K12, but significantly also of H4K8, H4K91 and H2AK5. Dimethylation of H3K79 was also selectively induced at target promoters. A majority of target promoters showed co-induction of multiple marks - in various combinations - correlating with recruitment of the two HATs tested (Tip60 and HBO1, incorporation of the histone variant H2A.Z and transcriptional activation. Based on this and previous findings, we surmise that Myc recruits the Tip60/p400 complex to achieve a coordinated histone acetylation/exchange reaction at activated promoters. Our data are also consistent with the additive and redundant role of multiple acetylation events in transcriptional activation.

  10. A simple histone code opens many paths to epigenetics.

    Directory of Open Access Journals (Sweden)

    Kim Sneppen

    Full Text Available Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers and can be recognized by nucleosome-binding proteins (readers. Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback--through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable

  11. A simple histone code opens many paths to epigenetics.

    Science.gov (United States)

    Sneppen, Kim; Dodd, Ian B

    2012-01-01

    Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers) and can be recognized by nucleosome-binding proteins (readers). Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback--through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable nucleosome

  12. Cloning, expression, purification and crystallization of Schizosaccharomyces pombe Set7, a putative histone methyltransferase.

    Science.gov (United States)

    Mevius, Damiaan E H F; Shen, Yunpeng; Morishita, Masayo; di Luccio, Eric

    2016-04-01

    Dysfunction of histone-modifying enzymes affects chromatin regulation and is involved in carcinogenesis, tumour progression and other diseases. Histone methyltransferases are a family of key histone-modifying enzymes, but their structures, functions and mechanisms are incompletely understood, thus constraining drug-design efforts. Here, preliminary steps towards structure-function studies of Schizosaccharomyces pombe Set7, a putative histone methyltransferase and the first yeast full-length SET-domain-containing protein to be studied using X-ray crystallography, are reported. The methods from cloning to X-ray diffraction and phasing are discussed and the results will aid in prospective studies of histone-modifying enzymes.

  13. Histone H3.3 mutations: a variant path to cancer.

    Science.gov (United States)

    Yuen, Benjamin T K; Knoepfler, Paul S

    2013-11-11

    A host of cancer types exhibit aberrant histone modifications. Recently, distinct and recurrent mutations in a specific histone variant, histone H3.3, have been implicated in a high proportion of malignant pediatric brain cancers. The presence of mutant H3.3 histone disrupts epigenetic posttranslational modifications near genes involved in cancer processes and in brain function. Here, we review possible mechanisms by which mutant H3.3 histones may act to promote tumorigenesis. Furthermore, we discuss how perturbations in normal H3.3 chromatin-related and epigenetic functions may more broadly contribute to the formation of human cancers. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Heavy-tailed chiral random matrix theory

    Energy Technology Data Exchange (ETDEWEB)

    Kanazawa, Takuya [iTHES Research Group and Quantum Hadron Physics Laboratory, RIKEN,Wako, Saitama, 351-0198 (Japan)

    2016-05-27

    We study an unconventional chiral random matrix model with a heavy-tailed probabilistic weight. The model is shown to exhibit chiral symmetry breaking with no bilinear condensate, in analogy to the Stern phase of QCD. We solve the model analytically and obtain the microscopic spectral density and the smallest eigenvalue distribution for an arbitrary number of flavors and arbitrary quark masses. Exotic behaviors such as non-decoupling of heavy flavors and a power-law tail of the smallest eigenvalue distribution are illustrated.

  15. Heavy-tailed chiral random matrix theory

    Science.gov (United States)

    Kanazawa, Takuya

    2016-05-01

    We study an unconventional chiral random matrix model with a heavy-tailed probabilistic weight. The model is shown to exhibit chiral symmetry breaking with no bilinear condensate, in analogy to the Stern phase of QCD. We solve the model analytically and obtain the microscopic spectral density and the smallest eigenvalue distribution for an arbitrary number of flavors and arbitrary quark masses. Exotic behaviors such as non-decoupling of heavy flavors and a power-law tail of the smallest eigenvalue distribution are illustrated.

  16. Heavy-tailed fractional Pearson diffusions.

    Science.gov (United States)

    Leonenko, N N; Papić, I; Sikorskii, A; Šuvak, N

    2017-11-01

    We define heavy-tailed fractional reciprocal gamma and Fisher-Snedecor diffusions by a non-Markovian time change in the corresponding Pearson diffusions. Pearson diffusions are governed by the backward Kolmogorov equations with space-varying polynomial coefficients and are widely used in applications. The corresponding fractional reciprocal gamma and Fisher-Snedecor diffusions are governed by the fractional backward Kolmogorov equations and have heavy-tailed marginal distributions in the steady state. We derive the explicit expressions for the transition densities of the fractional reciprocal gamma and Fisher-Snedecor diffusions and strong solutions of the associated Cauchy problems for the fractional backward Kolmogorov equation.

  17. The Oncogenic Polycomb Histone Methyltransferase EZH2Methylates Lysine 120 on Histone H2B and Competes Ubiquitination

    Directory of Open Access Journals (Sweden)

    Masaharu Kogure

    2013-11-01

    Full Text Available The histone methyltransferase enhancer of zeste 2 (EZH2 is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to histone H3 at lysine 27 (H3K27. We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on histone H2B (H2BK120. EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation- Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.

  18. Complete Workflow for Analysis of Histone Post-translational Modifications Using Bottom-up Mass Spectrometry: From Histone Extraction to Data Analysis.

    Science.gov (United States)

    Sidoli, Simone; Bhanu, Natarajan V; Karch, Kelly R; Wang, Xiaoshi; Garcia, Benjamin A

    2016-05-17

    Nucleosomes are the smallest structural unit of chromatin, composed of 147 base pairs of DNA wrapped around an octamer of histone proteins. Histone function is mediated by extensive post-translational modification by a myriad of nuclear proteins. These modifications are critical for nuclear integrity as they regulate chromatin structure and recruit enzymes involved in gene regulation, DNA repair and chromosome condensation. Even though a large part of the scientific community adopts antibody-based techniques to characterize histone PTM abundance, these approaches are low throughput and biased against hypermodified proteins, as the epitope might be obstructed by nearby modifications. This protocol describes the use of nano liquid chromatography (nLC) and mass spectrometry (MS) for accurate quantification of histone modifications. This method is designed to characterize a large variety of histone PTMs and the relative abundance of several histone variants within single analyses. In this protocol, histones are derivatized with propionic anhydride followed by digestion with trypsin to generate peptides of 5 - 20 aa in length. After digestion, the newly exposed N-termini of the histone peptides are derivatized to improve chromatographic retention during nLC-MS. This method allows for the relative quantification of histone PTMs spanning four orders of magnitude.

  19. Head/tail Breaks: A New Classification Scheme for Data with a Heavy-tailed Distribution

    CERN Document Server

    Jiang, Bin

    2012-01-01

    This paper introduces a new classification scheme - head/tail breaks - in order to find groupings or hierarchy for data with a heavy-tailed distribution. The heavy-tailed distributions are heavily right skewed, with a minority of large values in the head and a majority of small values in the tail, commonly characterized by a power law, a lognormal or an exponential function. For example, a country's population is often distributed in such a heavy-tailed manner, with a minority of people (e.g., 20 percent) in the countryside and the vast majority (e.g., 80 percent) in urban areas. This heavy-tailed distribution is also called scaling, hierarchy or scaling hierarchy. This new classification scheme partitions all of the data values around the mean into two parts and continues the process iteratively for the values (above the mean) in the head until the head part values are no longer heavy-tailed distributed. Thus, the number of classes and the class intervals are both naturally determined. We therefore claim tha...

  20. Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C

    DEFF Research Database (Denmark)

    Leurs, Ulrike; Lohse, Brian; Rand, Kasper Dyrberg

    2014-01-01

    Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging as the active sites of KDM1A-B and KDM-4A-D histone demethylases, respectively, are highly conserved. Most...... inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide...... sequence, or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation...

  1. Quantitative proteomic analysis of post-translational modifications of human histones

    DEFF Research Database (Denmark)

    Beck, Hans Christian; Nielsen, Eva C; Matthiesen, Rune

    2006-01-01

    software for qualitative and quantitative proteomic analysis of histones extracted from human small cell lung cancer cells. A total of 32 acetylations, methylations, and ubiquitinations were located in the human histones H2A, H2B, H3, and H4, including seven novel modifications. An LC-MSMS-based method...... was applied in a quantitative proteomic study of the dose-response effect of the histone deacetylase inhibitor (HDACi) PXD101 on histone acetylation in human cell cultures. Triplicate LC-MSMS runs at six different HDACi concentrations demonstrated that PXD101 affects acetylation of histones H2A, H2B, H3...... by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post...

  2. Predicting the targeting of tail-anchored proteins to subcellular compartments in mammalian cells.

    Science.gov (United States)

    Costello, Joseph L; Castro, Inês G; Camões, Fátima; Schrader, Tina A; McNeall, Doug; Yang, Jing; Giannopoulou, Evdokia-Anastasia; Gomes, Sílvia; Pogenberg, Vivian; Bonekamp, Nina A; Ribeiro, Daniela; Wilmanns, Matthias; Jedd, Gregory; Islinger, Markus; Schrader, Michael

    2017-05-01

    Tail-anchored (TA) proteins contain a single transmembrane domain (TMD) at the C-terminus that anchors them to the membranes of organelles where they mediate critical cellular processes. Accordingly, mutations in genes encoding TA proteins have been identified in a number of severe inherited disorders. Despite the importance of correctly targeting a TA protein to its appropriate membrane, the mechanisms and signals involved are not fully understood. In this study, we identify additional peroxisomal TA proteins, discover more proteins that are present on multiple organelles, and reveal that a combination of TMD hydrophobicity and tail charge determines targeting to distinct organelle locations in mammals. Specifically, an increase in tail charge can override a hydrophobic TMD signal and re-direct a protein from the ER to peroxisomes or mitochondria and vice versa. We show that subtle changes in those parameters can shift TA proteins between organelles, explaining why peroxisomes and mitochondria have many of the same TA proteins. This enabled us to associate characteristic physicochemical parameters in TA proteins with particular organelle groups. Using this classification allowed successful prediction of the location of uncharacterized TA proteins for the first time. © 2017. Published by The Company of Biologists Ltd.

  3. Electrokinetic remediation of copper mine tailings

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, H. K.; Rojo, A.; Ottosen, L. M.

    2009-07-01

    The heavy metal contamination from mining industry has become a growing problem both in chile and worldwide. This contamination includes large areas with soil pollution, contaminated rivers and continuous generation of mining waste deposits. The solid waste that will be analysed is mine tailings, which are the residual products after the flotation process in conventional sulphide copper mining. (Author)

  4. Review: Observations of recent comets, ion tails

    Science.gov (United States)

    Brandt, J. C.

    1976-01-01

    Photographic plates of the moving structures in the cometary tail are examined. Several divergent explanations for the case of comet Kohoutek are presented. It is suggested that these hypotheses be tested by observing the motion of the material spectroscopically by means of the Doppler effect.

  5. Zone-tailed Hawk (Buteo albonotatus)

    Science.gov (United States)

    Scott H. Stoleson; Giancarlo Sadoti

    2010-01-01

    The Zone-tailed Hawk (Buteo albonotatus) might well be dubbed "the Great Pretender" because it so closely resembles the ubiquitous Turkey Vulture (Cathartes aura) in appearance and behavior as to be frequently mistaken for it. In the border regions where it lives, it may be confused as well with another "Mexican" raptor, the Common Black-Hawk (...

  6. Nested head-tail Vlasov solver

    Directory of Open Access Journals (Sweden)

    A. Burov

    2014-02-01

    Full Text Available Nested head-tail is a Vlasov solver for transverse oscillations in multibunch beams. It takes into account azimuthal, radial, coupled-bunch, and beam-beam degrees of freedom affected by arbitrary dipole wakes, feedback damper,beam-beam effects and Landau damping.

  7. T-tail flutter analysis using Edge

    CSIR Research Space (South Africa)

    Van Zyl, Lourens H

    2011-11-01

    Full Text Available -tail. In reality, due to some a-symmetry in the grid, this was not quite achieved. The analyses consisted of a steady solution, followed by a prescribed, sine-squared, disturbance of 0.03 radians (corresponding to 10 mm lateral displacement at the fin top...

  8. Electrodialytic remediation of copper mine tailings

    DEFF Research Database (Denmark)

    Hansen, Henrik K.; Rojo, A.; Ottpsen, Lisbeth M.

    2005-01-01

    Mining activities in Chile have generated large amounts of solid waste, which have been deposited in mine tailing impoundments. These impoundments cause concern to the communities due to dam failures or natural leaching to groundwater and rivers.This work shows the laboratory results of nine...

  9. Controlled Impact Demonstration (CID) tail camera video

    Science.gov (United States)

    1984-01-01

    The Controlled Impact Demonstration (CID) was a joint research project by NASA and the FAA to test a survivable aircraft impact using a remotely piloted Boeing 720 aircraft. The tail camera movie is one shot running 27 seconds. It shows the impact from the perspective of a camera mounted high on the vertical stabilizer, looking forward over the fuselage and wings.

  10. Tailings segregation fundamentals from flow behaviour perspective

    Energy Technology Data Exchange (ETDEWEB)

    Mihiretu, Y.; Chalaturnyk, R. [Alberta Univ., Edmonton, AB (Canada). Dept. of Civil and Environmental Engineering, Geotechnical Centre; Scott, J.D. [Alberta Univ., Edmonton, AB (Canada). Dept. of Civil and Environmental Engineering, Geotechnical Centre

    2008-07-01

    This presentation focused on tailings segregation from a flow behaviour perspective. An introduction to conventional tailing disposal was first provided, followed by 2 definitions of segregation. The first defined segregation as the tendency of solid fractions to settle, creating a concentration gradient within the mass. The second definition explained segregation as the tendency for certain sizes or components with similar properties to preferentially collect in one or another physical zone of collective. For segregation to occur, there must be a difference in size, density, shape, and chemical affinity. Limitations exist because of the complex interaction of the characteristics; rudimentary know-how; lacking mechanics; and experimental difficulties and technical limitations. The experimental methodology and test materials were also presented with reference to kaolinite, silt size quartz particles, fine sand, tap water, and oil sands tailings materials. The presentation included several graphical charts and tables of geotechnical index properties; test matrix; rheological models; rheological characterization of kaolinite slurry at different solid content; rheological measurement; viscosity testing on tailings samples; temperature effect; yield stress measurement of thickener underflow and others. Rheological characterization was shown to have a fundamental application in the study of segregation. It was concluded that vane rheometry could quickly and easily characterize a slurry. tabs., figs.

  11. Primary stabilisation for tail avulsion in 15 cats.

    Science.gov (United States)

    Caraty, J; Hassoun, R; Meheust, P

    2018-01-01

    To evaluate the effects of a primary tail stabilisation technique in relieving pain and supporting nerve recovery in cats that have lost voluntary motor function and pain sensation in the tail without caudal nerve transection. Retrospective review of medical records and preoperative diagnostic tests, including clinical examination results and tail radiographs of cats suffering from tail avulsion with loss of pain perception in the tail between 2009 and 2015. Cats with open tail fracture, tail wounds that necessitated an amputation or caudal nerve root transection were excluded. Tail reconstruction was performed, after surgical exploration, with two nylon sutures. Fifteen cats were included, all of which had lost voluntary motor function in the tail and 8 of 15 were urinary incontinent. After surgery, 11 cats recovered voluntary tail function and pain sensation within 14 to 90 days (mean 39 days). Five of the eight previously incontinent cats recovered urinary continence within a month of surgery. The reported method of primary tail stabilisation is associated with recovery of lost function in the majority of cats presenting with tail avulsions, loss of pain sensation in the tail but without caudal nerve root transection. A comparison study is required to determine whether these results are superior to conservative management. © 2017 British Small Animal Veterinary Association.

  12. Flight costs of long, sexually selected tails in hummingbirds.

    Science.gov (United States)

    Clark, Christopher James; Dudley, Robert

    2009-06-07

    The elongated tails adorning many male birds have traditionally been thought to degrade flight performance by increasing body drag. However, aerodynamic interactions between the body and tail can be substantial in some contexts, and a short tail may actually reduce rather than increase overall drag. To test how tail length affects flight performance, we manipulated the tails of Anna's hummingbirds (Calypte anna) by increasing their length with the greatly elongated tail streamers of the red-billed streamertail (Trochilus polytmus) and reducing their length by removing first the rectrices and then the entire tail (i.e. all rectrices and tail covert feathers). Flight performance was measured in a wind tunnel by measuring (i) the maximum forward speed at which the birds could fly and (ii) the metabolic cost of flight while flying at airspeeds from 0 to 14 m s(-1). We found a significant interaction effect between tail treatment and airspeed: an elongated tail increased the metabolic cost of flight by up to 11 per cent, and this effect was strongest at higher flight speeds. Maximum flight speed was concomitantly reduced by 3.4 per cent. Also, removing the entire tail decreased maximum flight speed by 2 per cent, suggesting beneficial aerodynamic effects for tails of normal length. The effects of elongation are thus subtle and airspeed-specific, suggesting that diversity in avian tail morphology is associated with only modest flight costs.

  13. Effects of tail docking on behavior of confined feedlot cattle.

    Science.gov (United States)

    Kroll, L K; Grooms, D L; Siegford, J M; Schweihofer, J P; Daigle, C L; Metz, K; Ladoni, M

    2014-10-01

    Tail tip injuries occur in some feedlot cattle housed in slatted-floor facilities typically found in the midwestern United States. The practice of tail docking cattle on entry into these feedlot facilities was initiated to prevent tail injuries. Tail docking is a welfare concern from the standpoint that an important method of fly avoidance is removed and the tail docking procedure is painful and often excludes local anesthesia or extended analgesia. The primary objective of this study was to describe the behavioral responses of feedlot cattle following tail docking. Thirty-six heifers were randomly assigned to 1 of 2 treatment groups: docked (DK) or control (CN). All calves received an epidural following surgical preparation of the sacrococcygeal area and postoperative intravenous flunixin meglumine. A portion of the tail of DK calves was removed using pruning shears. An elastrator band was placed near the tail tip for hemostasis and tail tips were sprayed with fly spray. IceQube accelerometers collected step counts, motion index, lying time, lying bouts, and lying bout duration during d -4 through 13. Direct observations of cattle behavior were performed on d 0, 1, and 2. Step counts of DK calves were increased (P tail docking, DK calves had increased lying bouts per hour (1.7 vs. 0.9 on d 0; P tails more (P tail-docked feedlot cattle. We recommend that alternative strategies to reduce tail tip injury be explored.

  14. Tailings research at Shell's Muskeg River mine tailings testing facility

    Energy Technology Data Exchange (ETDEWEB)

    Matthews, J.; Masala, S. [Shell Canada Ltd., Calgary, AB (Canada). Oil Sands Division

    2009-07-01

    This presentation discussed a non-segregating tailings (NST) pilot program conducted at the Muskeg River Mine tailings test facility. NST deposition performance and deposit characteristics were evaluated. NST fines are stored in the pore spaces in sandy deposits. Coagulants are used to enhance the yield stress of fine mineral solids-water suspension and improve the retention of fines in sand deposit pores. High solids slurries reduce fine mineral solids separation from the granular matrix. The use of NST increases the maximum volumetric storage of sand and clay fines and reduces the fluid fine tailings inventory. Performance metrics for NST include deposit homogeneity, overall fines capture, the time to consolidation, and strength after consolidation. It was concluded that NST is an effective means of reducing the rate of production of fluid fine tailings at oil sands mining operations. A simplified NST process flowsheet was presented, as well as photographs of NST slurry depositions. tabs., figs.

  15. Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory

    OpenAIRE

    Hawk, Joshua D.; Florian, Cédrick; Abel, Ted

    2011-01-01

    Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance long-term memory have focused on the fear-conditioning task using broad-spectrum HDAC inhibitors. We have found that post-training intrahippocampal a...

  16. Ottawa National Wildlife Refuge : White-tailed Deer Hunting Plan

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This White-tailed Deer Hunting Plan for Ottawa NWR provides an introduction to the Refuge, summarizes Refuge objectives, assesses the white-tailed deer population on...

  17. Costs associated with tail autotomy in an ambush foraging lizard ...

    African Journals Online (AJOL)

    . Most studies on the effects of tail loss have focused on active foraging lizards, but few data exist for ambush foraging lizards. We investigated potential costs associated with tail autotomy in an extreme ambush foraging cordylid lizard, ...

  18. Collecting Tail Hair Follicle for Bison DNA Sample

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — SOP guiding collection and processing of tail hair follicles from Bison for genetics analysis. Provides stepwise instructions and guidance on how to collect tail...

  19. Histone deacetylase inhibitors in the treatment of lymphoma.

    Science.gov (United States)

    Lemoine, Manuela; Younes, Anas

    2010-11-01

    Histone deacetylases (HDACs) play an important role in the regulation of gene expression. In addition to histones, HDACs can modulate the function of many other proteins involved in the regulation of cell survival and proliferation, angiogenesis, inflammation, and immunity. Deregulated HDACs have been shown to be commonly associated with many types of cancer, and are considered promising targets for cancer therapy. Several HDAC inhibitors are in clinical trials as monotherapies or in combination with other anticancer agents, but only two such inhibitors -- vorinostat (suberoylanilide hydroxamic acid) and romidepsin (depsipeptide) -- have been approved by the US Food and Drug Administration for treating relapsed cutaneous T-cell lymphoma. Other HDAC inhibitors, such as belinostat (PXD101), mocetinostat (MGCD0103), entinostat (SNDX-275), and panobinostat (LBH589), are currently in clinical development. This review focuses on the use of HDAC inhibitors in the treatment of relapsed lymphoma.

  20. Understanding the relationship between DNA methylation and histone lysine methylation☆

    Science.gov (United States)

    Rose, Nathan R.; Klose, Robert J.

    2014-01-01

    DNA methylation acts as an epigenetic modification in vertebrate DNA. Recently it has become clear that the DNA and histone lysine methylation systems are highly interrelated and rely mechanistically on each other for normal chromatin function in vivo. Here we examine some of the functional links between these systems, with a particular focus on several recent discoveries suggesting how lysine methylation may help to target DNA methylation during development, and vice versa. In addition, the emerging role of non-methylated DNA found in CpG islands in defining histone lysine methylation profiles at gene regulatory elements will be discussed in the context of gene regulation. This article is part of a Special Issue entitled: Methylation: A Multifaceted Modification — looking at transcription and beyond. PMID:24560929

  1. The Oncoprotein BRD4-NUT Generates Aberrant Histone Modification Patterns.

    Directory of Open Access Journals (Sweden)

    Barry M Zee

    Full Text Available Defects in chromatin proteins frequently manifest in diseases. A striking case of a chromatin-centric disease is NUT-midline carcinoma (NMC, which is characterized by expression of NUT as a fusion partner most frequently with BRD4. ChIP-sequencing studies from NMC patients revealed that BRD4-NUT (B4N covers large genomic regions and elevates transcription within these domains. To investigate how B4N modulates chromatin, we performed affinity purification of B4N when ectopically expressed in 293-TREx cells and quantified the associated histone posttranslational modifications (PTM using proteomics. We observed significant enrichment of acetylation particularly on H3 K18 and of combinatorial patterns such as H3 K27 acetylation paired with K36 methylation. We postulate that B4N complexes override the preexisting histone code with new PTM patterns that reflect aberrant transcription and that epigenetically modulate the nucleosome environment toward the NMC state.

  2. Charged Domain Walls

    OpenAIRE

    Campanelli, L.; Cea, P.; Fogli, G. L.; Tedesco, L.

    2003-01-01

    In this paper we investigate Charged Domain Walls (CDW's), topological defects that acquire surface charge density $Q$ induced by fermion states localized on the walls. The presence of an electric and magnetic field on the walls is also discussed. We find a relation in which the value of the surface charge density $Q$ is connected with the existence of such topological defects.

  3. The histone code of Toxoplasma gondii comprises conserved and unique posttranslational modifications.

    Science.gov (United States)

    Nardelli, Sheila C; Che, Fa-Yun; Silmon de Monerri, Natalie C; Xiao, Hui; Nieves, Edward; Madrid-Aliste, Carlos; Angel, Sergio O; Sullivan, William J; Angeletti, Ruth H; Kim, Kami; Weiss, Louis M

    2013-12-10

    Epigenetic gene regulation has emerged as a major mechanism for gene regulation in all eukaryotes. Histones are small, basic proteins that constitute the major protein component of chromatin, and posttranslational modifications (PTM) of histones are essential for epigenetic gene regulation. The different combinations of histone PTM form the histone code for an organism, marking functional units of chromatin that recruit macromolecular complexes that govern chromatin structure and regulate gene expression. To characterize the repertoire of Toxoplasma gondii histone PTM, we enriched histones using standard acid extraction protocols and analyzed them with several complementary middle-down and bottom-up proteomic approaches with the high-resolution Orbitrap mass spectrometer using collision-induced dissociation (CID), higher-energy collisional dissociation (HCD), and/or electron transfer dissociation (ETD) fragmentation. We identified 249 peptides with unique combinations of PTM that comprise the T. gondii histone code. T. gondii histones share a high degree of sequence conservation with human histones, and many modifications are conserved between these species. In addition, T. gondii histones have unique modifications not previously identified in other species. Finally, T. gondii histones are modified by succinylation, propionylation, and formylation, recently described histone PTM that have not previously been identified in parasitic protozoa. The characterization of the T. gondii histone code will facilitate in-depth analysis of how epigenetic regulation affects gene expression in pathogenic apicomplexan parasites and identify a new model system for elucidating the biological functions of novel histone PTM. Toxoplasma gondii is among the most common parasitic infections in humans. The transition between the different stages of the T. gondii life cycle are essential for parasite virulence and survival. These differentiation events are accompanied by significant

  4. Genome-wide analysis of regions similar to promoters of histone genes

    KAUST Repository

    Chowdhary, Rajesh

    2010-05-28

    Background: The purpose of this study is to: i) develop a computational model of promoters of human histone-encoding genes (shortly histone genes), an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes.Results: We successfully developed a histone promoter model using a comprehensive collection of histone genes. Based on leave-one-out cross-validation test, the model produced good prediction accuracy (94.1% sensitivity, 92.6% specificity, and 92.8% positive predictive value). We used this model to predict across the genome a number of genes that shared similar promoter structures with the histone gene promoters. We thus hypothesize that these predicted genes could be coregulated with histone genes. This hypothesis matches well with the available gene expression, gene ontology, and pathways data. Jointly with promoters of the above-mentioned genes, we found a large number of intergenic regions with similar structure as histone promoters.Conclusions: This study represents one of the most comprehensive computational analyses conducted thus far on a genome-wide scale of promoters of human histone genes. Our analysis suggests a number of other human genes that share a high similarity of promoter structure with the histone genes and thus are highly likely to be coregulated, and consequently coexpressed, with the histone genes. We also found that there are a large number of intergenic regions across the genome with their structures similar to promoters of histone genes. These regions may be promoters of yet unidentified genes, or may represent remote control regions that

  5. ESTIMATION OF FILTRATION CAPACITY OF POSTFLOTATION TAILINGS EMBEDDED IN DAMS OF TAILINGS DEPOSITION SITES

    Directory of Open Access Journals (Sweden)

    Wojciech Tschuschke

    2015-10-01

    Full Text Available Construction of very big mine tailings deposition sites, such as postflotation tailings ponds, is a complicated engineering task, in which several technical and environmental problems need to be solved. Designing, construction and operation of such an object applying the monitoring method consists in the verification of design assumptions based on continuous observations. One of the primary tasks of monitoring while the deposition site is being filled with tailings is to control quality of the formed dam embankments, as the structural element of the object responsible for its stability. In order to use material selected from deposited tailings in the construction of dams it is necessary to define grain size and compaction criteria, which directly affect load bearing capacity and deformation of the structure. For this reason main control tests include the analyses of grain size distribution and physical properties of the material embedded in the dams. These data may also be used to estimate filtration capacity of the embankment. A lack of drainage, causing accumulation of water within the embankment, may potentially deteriorate stability conditions. This paper presents the use of empirical formulas, i.e. formulas typically applied to natural soils, to assess permeability coefficient of tailings. A simple empirical formula was also proposed for the estimation of permeability coefficient of tailings based on grain size and compaction parameters determined in routine quality tests of constructed dam embankments.

  6. Histone Methylation in Nickel-Smelting Industrial Workers

    OpenAIRE

    Li Ma; Yana Bai; Hongquan Pu; Faxiang Gou; Min Dai; Hui Wang; Jie He; Tongzhang Zheng; Ning Cheng

    2015-01-01

    Background Nickel is an essential trace metal naturally found in the environment. It is also common in occupational settings, where it associates with various levels of both occupational and nonoccupational exposure In vitro studies have shown that nickel exposure can lead to intracellular accumulation of Ni2+, which has been associated with global decreases in DNA methylation, increases in chromatin condensation, reductions in H3K9me2, and elevated levels of H3K4me3. Histone modifications pl...

  7. Histone demethylase JMJD5 is essential for embryonic development

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Sangphil [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 (United States); Janknecht, Ralf, E-mail: ralf-janknecht@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 (United States)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Histone demethylase JMJD5 is essential for embryogenesis. Black-Right-Pointing-Pointer Transcription of tumor suppressor p53 is upregulated in JMJD5 knockout embryos. Black-Right-Pointing-Pointer JMJD5 may antagonize p53-dependent growth inhibition and apoptosis. Black-Right-Pointing-Pointer JMJD5 is overexpressed in leukemias and breast cancer. -- Abstract: Histone lysine methylation is pivotal in regulating chromatin structure and thus profoundly affects the transcriptome. JMJD5 (jumonji C domain-containing 5) is a histone demethylase that specifically removes methyl moieties from dimethylated lysine 36 on histone H3 and exerts a pro-proliferative effect on breast cancer cells. Here, we generated JMJD5 knockout mice in order to study the physiological significance of this enzyme. Whereas heterozygous knockout mice displayed no overt phenotype, homozygous JMJD5 knockouts died around day 10 of embryonal development. JMJD5{sup -/-} embryos showed delayed development already at E8.5 and were actively resorbed at E10.5. While strong JMJD5 expression was observed only in the yolk sac at E8.5, JMJD5 was robustly expressed in E10.5 embryos at several sites, including the heart and eye. Lack of JMJD5 resulted in transcriptional upregulation of the tumor suppressor p53. Concurrently, the cell cycle inhibitor p21 and the pro-apoptotic molecule Noxa, both of which are prominent p53 target genes, became strongly upregulated in JMJD5{sup -/-} embryos. Collectively, our data indicate that JMJD5 is essential during embryonal development and a repressor of p53 expression. The latter suggests that JMJD5 has oncogenic activity and accordingly JMJD5 is upregulated in leukemias and breast cancer.

  8. Targeting Histone Abnormality in Triple Negative Breast Cancer

    Science.gov (United States)

    2016-08-01

    Zawacki K, Podewils LJ, Cohen G and McCorkle R. Exercise manages fatigue during breast cancer treatment: a randomized controlled trial. Psycho...27249683. 301. Bhargava R, Davidson NE. "Take two"? The role of second opinions for breast biopsy specimens. Bmj . 2016;353:i3256, 2016. PMID: 27339037...deacetylase regulates muscle differentiation. Nature 2000; 408: 106–111. 18 Martin M, Kettmann R, Dequiedt F. Class IIa histone deacetylases: conducting

  9. Tail-assisted pitch control in lizards, robots and dinosaurs.

    Science.gov (United States)

    Libby, Thomas; Moore, Talia Y; Chang-Siu, Evan; Li, Deborah; Cohen, Daniel J; Jusufi, Ardian; Full, Robert J

    2012-01-04

    In 1969, a palaeontologist proposed that theropod dinosaurs used their tails as dynamic stabilizers during rapid or irregular movements, contributing to their depiction as active and agile predators. Since then the inertia of swinging appendages has been implicated in stabilizing human walking, aiding acrobatic manoeuvres by primates and rodents, and enabling cats to balance on branches. Recent studies on geckos suggest that active tail stabilization occurs during climbing, righting and gliding. By contrast, studies on the effect of lizard tail loss show evidence of a decrease, an increase or no change in performance. Application of a control-theoretic framework could advance our general understanding of inertial appendage use in locomotion. Here we report that lizards control the swing of their tails in a measured manner to redirect angular momentum from their bodies to their tails, stabilizing body attitude in the sagittal plane. We video-recorded Red-Headed Agama lizards (Agama agama) leaping towards a vertical surface by first vaulting onto an obstacle with variable traction to induce a range of perturbations in body angular momentum. To examine a known controlled tail response, we built a lizard-sized robot with an active tail that used sensory feedback to stabilize pitch as it drove off a ramp. Our dynamics model revealed that a body swinging its tail experienced less rotation than a body with a rigid tail, a passively compliant tail or no tail. To compare a range of tails, we calculated tail effectiveness as the amount of tailless body rotation a tail could stabilize. A model Velociraptor mongoliensis supported the initial tail stabilization hypothesis, showing as it did a greater tail effectiveness than the Agama lizards. Leaping lizards show that inertial control of body attitude can advance our understanding of appendage evolution and provide biological inspiration for the next generation of manoeuvrable search-and-rescue robots.

  10. A unified phylogeny-based nomenclature for histone variants.

    Science.gov (United States)

    Talbert, Paul B; Ahmad, Kami; Almouzni, Geneviève; Ausió, Juan; Berger, Frederic; Bhalla, Prem L; Bonner, William M; Cande, W Zacheus; Chadwick, Brian P; Chan, Simon W L; Cross, George A M; Cui, Liwang; Dimitrov, Stefan I; Doenecke, Detlef; Eirin-López, José M; Gorovsky, Martin A; Hake, Sandra B; Hamkalo, Barbara A; Holec, Sarah; Jacobsen, Steven E; Kamieniarz, Kinga; Khochbin, Saadi; Ladurner, Andreas G; Landsman, David; Latham, John A; Loppin, Benjamin; Malik, Harmit S; Marzluff, William F; Pehrson, John R; Postberg, Jan; Schneider, Robert; Singh, Mohan B; Smith, M Mitchell; Thompson, Eric; Torres-Padilla, Maria-Elena; Tremethick, David John; Turner, Bryan M; Waterborg, Jakob Harm; Wollmann, Heike; Yelagandula, Ramesh; Zhu, Bing; Henikoff, Steven

    2012-06-21

    Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  11. Distinct site specificity of two pea histone deacetylase complexes.

    Science.gov (United States)

    Clemente, S; Franco, L; López-Rodas, G

    2001-09-04

    We report on the site specificity of two intact pea histone deacetylase complexes. HD1 deacetylates lysines 5 and 16 of H4 in the order K16 > K5, while in the case of H3 the preferred order is K4 > K18 approximately K9. The specificity of the HD2 complex is markedly different. The preferred residues in H4 are K8 approximately K5 > K16, while in H3 deacetylation, the complex HD2 prefers sites 4 and 18. To obtain these results, we have used a novel procedure based on the SPOT technique, a method to synthesize peptides on membrane supports. Different sets of membranes with sequentially overlapping histone peptides containing acetylated lysines in the sites corresponding to all in vivo acetylatable residues were incubated with the complexes. The acetyl groups removed by the deacetylase activity were then replaced by radioactive acetate by treating the membranes with labeled acetic anhydride. The subsequent counting of the membranes allows the quantification of the acetate removal in the histone deacetylase reaction in a way that circumvents some of the inconveniences of other available procedures.

  12. A unified phylogeny-based nomenclature for histone variants

    Directory of Open Access Journals (Sweden)

    Talbert Paul B

    2012-06-01

    Full Text Available Abstract Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  13. Specificity of antibodies raised against triacetylated histone H4.

    Science.gov (United States)

    Muller, S; Isabey, A; Couppez, M; Plaue, S; Sommermeyer, G; Van Regenmortel, M H

    1987-07-01

    Ten monoclonal antibodies (mAbs) were obtained by immunizing animals with triacetylated histone H4 from cuttle-fish. The fine specificity of these antibodies was studied using various populations of acetylated H4, (H3H4)2 tetramers and histone octamers as well as with acetylated and nonacetylated peptides of H4. None of these mAbs were found to recognize triacetylated H4. Only five of them bound to diacetylated, monoacetylated and nonacetylated H4. One antibody was specific for H4 associated in the form of histone octamers and did not bind to any nonacetylated or acetylated form of H4 monomers. Eight of the antibodies were specific for residues situated in the region 9-23 of H4. None of the mAbs was completely specific for acetylated forms of H4. In contrast, antisera raised in rabbits against triacetylated H4 reacted strongly with tri and diacetylated H4, weakly with monoacetylated H4 and barely or not at all with nonacetylated H4.

  14. Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Castonguay, Zachary; Auger, Christopher; Thomas, Sean C.; Chahma, M’hamed; Appanna, Vasu D., E-mail: vappanna@laurentian.ca

    2014-11-07

    Highlights: • Nuclear LDH is up-regulated under oxidative stress. • SIRT1 is co-immunoprecipitated bound to nuclear LDH. • Nuclear LDH is involved in histone deacetylation and epigenetics. - Abstract: It is becoming increasingly apparent that the nucleus harbors metabolic enzymes that affect genetic transforming events. Here, we describe a nuclear isoform of lactate dehydrogenase (nLDH) and its ability to orchestrate histone deacetylation by controlling the availability of nicotinamide adenine dinucleotide (NAD{sup +}), a key ingredient of the sirtuin-1 (SIRT1) deacetylase system. There was an increase in the expression of nLDH concomitant with the presence of hydrogen peroxide (H{sub 2}O{sub 2}) in the culture medium. Under oxidative stress, the NAD{sup +} generated by nLDH resulted in the enhanced deacetylation of histones compared to the control hepatocytes despite no discernable change in the levels of SIRT1. There appeared to be an intimate association between nLDH and SIRT1 as these two enzymes co-immunoprecipitated. The ability of nLDH to regulate epigenetic modifications by manipulating NAD{sup +} reveals an intricate link between metabolism and the processing of genetic information.

  15. Compendium of aberrant DNA methylation and histone modifications in cancer.

    Science.gov (United States)

    Hattori, Naoko; Ushijima, Toshikazu

    2014-12-05

    Epigenetics now refers to the study or research field related to DNA methylation and histone modifications. Historically, global DNA hypomethylation was first revealed in 1983, and, after a decade, silencing of a tumor suppressor gene by regional DNA hypermethylation was reported. After the proposal of the histone code in the 2000s, alterations of histone methylation were also identified in cancers. Now, it is established that aberrant epigenetic alterations are involved in cancer development and progression, along with mutations and chromosomal losses. Recent cancer genome analyses have revealed a large number of mutations of epigenetic modifiers, supporting their important roles in cancer pathogenesis. Taking advantage of the reversibility of epigenetic alterations, drugs targeting epigenetic regulators and readers have been developed for restoration of normal pattern of the epigenome, and some have already demonstrated clinical benefits. In addition, DNA methylation of specific marker genes can be used as a biomarker for cancer diagnosis, including risk diagnosis, detection of cancers, and pathophysiological diagnosis. In this paper, we will summarize the major concepts of cancer epigenetics, placing emphasis on history. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Finding associations among histone modifications using sparse partial correlation networks.

    Directory of Open Access Journals (Sweden)

    Julia Lasserre

    Full Text Available Histone modifications are known to play an important role in the regulation of transcription. While individual modifications have received much attention in genome-wide analyses, little is known about their relationships. Some authors have built Bayesian networks of modifications, however most often they have used discretized data, and relied on unrealistic assumptions such as the absence of feedback mechanisms or hidden confounding factors. Here, we propose to infer undirected networks based on partial correlations between histone modifications. Within the partial correlation framework, correlations among two variables are controlled for associations induced by the other variables. Partial correlation networks thus focus on direct associations of histone modifications. We apply this methodology to data in CD4+ cells. The resulting network is well supported by common knowledge. When pairs of modifications show a large difference between their correlation and their partial correlation, a potential confounding factor is identified and provided as explanation. Data from different cell types (IMR90, H1 is also exploited in the analysis to assess the stability of the networks. The results are remarkably similar across cell types. Based on this observation, the networks from the three cell types are integrated into a consensus network to increase robustness. The data and the results discussed in the manuscript can be found, together with code, on http://spcn.molgen.mpg.de/index.html.

  17. measurement of radionuclides in processed mine tailings in jos ...

    African Journals Online (AJOL)

    DR. AMINU

    radioactivity and therefore required different methods of management (GAEC, 2005). Tailings also known as tailings pile, tails leach residue or slickens are the materials left over after the process of separating the valuable fraction from the worthless fraction of an ore. These are waste products that have no financial gain to a.

  18. 14 CFR 23.497 - Supplementary conditions for tail wheels.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Supplementary conditions for tail wheels... Structure Ground Loads § 23.497 Supplementary conditions for tail wheels. In determining the ground loads on the tail wheel and affected supporting structures, the following apply: (a) For the obstruction load...

  19. 14 CFR 23.745 - Nose/tail wheel steering.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Nose/tail wheel steering. 23.745 Section 23.745 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... Landing Gear § 23.745 Nose/tail wheel steering. (a) If nose/tail wheel steering is installed, it must be...

  20. 14 CFR 25.497 - Tail-wheel yawing.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Tail-wheel yawing. 25.497 Section 25.497... STANDARDS: TRANSPORT CATEGORY AIRPLANES Structure Ground Loads § 25.497 Tail-wheel yawing. (a) A vertical ground reaction equal to the static load on the tail wheel, in combination with a side component of equal...