Greenblatt, Sarah M.; Nimer, Stephen D.
Hematopoiesis is a tightly regulated process involving the control of gene expression that directs the transition from hematopoietic stem and progenitor cells to terminally differentiated blood cells. In leukemia, the processes directing self-renewal, differentiation, and progenitor cell expansion are disrupted, leading to the accumulation of immature, non-functioning malignant cells. Insights into these processes have come in stages, based upon technological advances in genetic analyses, bioinformatics, and biological sciences. The first cytogenetic studies of leukemic cells identified chromosomal translocations that generate oncogenic fusion proteins, and most commonly affect regulators of transcription. This was followed by the discovery of recurrent somatic mutations in genes encoding regulators of the signal transduction pathways that control cell proliferation and survival. Recently, studies of global changes in methylation and gene expression have led to the understanding that the output of transcriptional regulators and the proliferative signaling pathways, are ultimately influenced by chromatin structure. Candidate gene, whole genome, and whole exome sequencing studies have identified recurrent somatic mutations in genes encoding epigenetic modifiers in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). In contrast to the two hit model of leukemogenesis, emerging evidence suggests that these epigenetic modifiers represent a class of mutations that are critical to the development of leukemia and affect the regulation of various other oncogenic pathways. In this review, we discuss the range of recurrent, somatic mutations in epigenetic modifiers found in leukemia and how these modifiers relate to the classical leukemogenic pathways that lead to impaired cell differentiation and aberrant self-renewal and proliferation. PMID:24609046
S. Henikoff (Steven); F.G. Grosveld (Frank)
textabstractOn 11 to 13 March 2013, BioMed Central will be hosting its inaugural conference, Epigenetics & Chromatin: Interactions and Processes, at Harvard Medical School, Cambridge, MA, USA. Epigenetics & Chromatin has now launched a special article series based on the general themes of the
Christopher Ian Cazzonelli
Full Text Available Thigmomorphogenesis is viewed as being a response process of acclimation to short repetitive bursts of mechanical stimulation or touch. The underlying molecular mechanisms that coordinate changes in how touch signals lead to long-term morphological changes are enigmatic. Touch responsive gene expression is rapid and transient, and no transcription factor or DNA regulatory motif has been reported that could confer a genome wide mechanical stimulus. We report here on a chromatin modifying enzyme, SDG8/ASHH2, which can regulate the expression of many touch responsive genes identified in Arabidopsis. SDG8 is required for the permissive expression of touch induced genes; and the loss of function of sdg8 perturbs the maximum levels of induction on selected touch gene targets. SDG8 is required to maintain permissive H3K4 trimethylation marks surrounding the Arabidopsis touch-inducible gene TOUCH 3 (TCH3, which encodes a calmodulin-like protein (CML12. The gene neighbouring was also slightly down regulated, revealing a new target for SDG8 mediated chromatin modification. Finally, sdg8 mutants show perturbed morphological response to wind-agitated mechanical stimuli, implicating an epigenetic memory-forming process in the acclimation response of thigmomorphogenesis.
David-Rus, Diana; Mukhopadhyay, Swagatam; Lebowitz, Joel L; Sengupta, Anirvan M
Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.
Fog, Cathrine K; Jensen, Klaus T; Lund, Anders Henrik
-despite the fact that all cells in the organism contain the same genetic information. A large amount of data gathered over the last decades has demonstrated that deregulation of chromatin-modifying proteins is etiologically involved in the development and progression of cancer. Here we discuss how epigenetic...... alterations influence cancer development and review known cancer-associated alterations in chromatin-modifying proteins....
Dayarian, Adel; Sengupta, Anirvan M.
Epigenetic mechanisms of silencing via heritable chromatin modifications play a major role in gene regulation and cell fate specification. We consider a model of epigenetic chromatin silencing in budding yeast and study the bifurcation diagram and characterize the bistable and the monostable regimes. The main focus of this paper is to examine how the perturbations altering the activity of histone modifying enzymes affect the epigenetic states. We analyze the implications of having the total number of silencing proteins, given by the sum of proteins bound to the nucleosomes and the ones available in the ambient, to be constant. This constraint couples different regions of chromatin through the shared reservoir of ambient silencing proteins. We show that the response of the system to perturbations depends dramatically on the titration effect caused by the above constraint. In particular, for a certain range of overall abundance of silencing proteins, the hysteresis loop changes qualitatively with certain jump replaced by continuous merger of different states. In addition, we find a nonmonotonic dependence of gene expression on the rate of histone deacetylation activity of Sir2. We discuss how these qualitative predictions of our model could be compared with experimental studies of the yeast system under anti-silencing drugs.
Reid, Michael A; Dai, Ziwei; Locasale, Jason W
The substrates used to modify nucleic acids and chromatin are affected by nutrient availability and the activity of metabolic pathways. Thus, cellular metabolism constitutes a fundamental component of chromatin status and thereby of genome regulation. Here we describe the biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics, discuss the functional roles of this interplay in developmental and cancer biology, and present future directions in this rapidly emerging area.
Lesne, Annick; Foray, Nicolas; Cathala, Guy; Forné, Thierry; Wong, Hua; Victor, Jean-Marc
The notion of allostery introduced for proteins about fifty years ago has been extended since then to DNA allostery, where a locally triggered DNA structural transition remotely controls other DNA-binding events. We further extend this notion and propose that chromatin fiber allosteric transitions, induced by histone-tail covalent modifications, may play a key role in transcriptional regulation. We present an integrated scenario articulating allosteric mechanisms at different scales: allosteric transitions of the condensed chromatin fiber induced by histone-tail acetylation modify the mechanical constraints experienced by the embedded DNA, thus possibly controlling DNA-binding of allosteric transcription factors or further allosteric mechanisms at the linker DNA level. At a higher scale, different epigenetic constraints delineate different statistically dominant subsets of accessible chromatin fiber conformations, which each favors the assembly of dedicated regulatory complexes, as detailed on the emblematic example of the mouse Igf2-H19 gene locus and its parental imprinting. This physical view offers a mechanistic and spatially structured explanation of the observed correlation between transcriptional activity and histone modifications. The evolutionary origin of allosteric control supports to speak of an ‘epigenetic code’, by which events involved in transcriptional regulation are encoded in histone modifications in a context-dependent way.
Bushey, Ashley M.; Dorman, Elizabeth R.; Corces, Victor G.
Enhancer-blocking insulators are DNA elements that disrupt the communication between a regulatory sequence, such as an enhancer or a silencer, and a promoter. Insulators participate in both transcriptional regulation and global nuclear organization, two features of chromatin that are thought to be maintained from one generation to the next through epigenetic mechanisms. Furthermore, there are many regulatory mechanisms in place that enhance or hinder insulator activity. These modes of regulation could be used to establish cell-type specific insulator activity that is epigenetically inherited along a cell and/or organismal lineage. This review will discuss the evidence for epigenetic inheritance and regulation of insulator function. PMID:18851828
Bey, Till; Jamge, Suraj; Klemme, Sonja; Komar, Dorota Natalia; Gall, Le Sabine; Mikulski, Pawel; Schmidt, Martin; Zicola, Johan; Berr, Alexandre
In January 2016, the first Epigenetic and Chromatin Regulation of Plant Traits conference was held in Strasbourg, France. An all-star lineup of speakers, a packed audience of 130 participants from over 20 countries, and a friendly scientific atmosphere contributed to make this conference a
Allshire, Robin C.; Ekwall, Karl
This article discusses the advances made in epigenetic research using the model organism fission yeast Schizosaccharomyces pombe. S. pombe has been used for epigenetic research since the discovery of position effect variegation (PEV). This is a phenomenon in which a transgene inserted within heterochromatin is variably expressed, but can be stably inherited in subsequent cell generations. PEV occurs at centromeres, telomeres, ribosomal DNA (rDNA) loci, and mating-type regions of S. pombe chromosomes. Heterochromatin assembly in these regions requires enzymes that modify histones and the RNA interference (RNAi) machinery. One of the key histone-modifying enzymes is the lysine methyltransferase Clr4, which methylates histone H3 on lysine 9 (H3K9), a classic hallmark of heterochromatin. The kinetochore is assembled on specialized chromatin in which histone H3 is replaced by the variant CENP-A. Studies in fission yeast have contributed to our understanding of the establishment and maintenance of CENP-A chromatin and the epigenetic activation and inactivation of centromeres. PMID:26134317
Allshire, Robin C; Ekwall, Karl
This article discusses the advances made in epigenetic research using the model organism fission yeast Schizosaccharomyces pombe. S. pombe has been used for epigenetic research since the discovery of position effect variegation (PEV). This is a phenomenon in which a transgene inserted within heterochromatin is variably expressed, but can be stably inherited in subsequent cell generations. PEV occurs at centromeres, telomeres, ribosomal DNA (rDNA) loci, and mating-type regions of S. pombe chromosomes. Heterochromatin assembly in these regions requires enzymes that modify histones and the RNA interference (RNAi) machinery. One of the key histone-modifying enzymes is the lysine methyltransferase Clr4, which methylates histone H3 on lysine 9 (H3K9), a classic hallmark of heterochromatin. The kinetochore is assembled on specialized chromatin in which histone H3 is replaced by the variant CENP-A. Studies in fission yeast have contributed to our understanding of the establishment and maintenance of CENP-A chromatin and the epigenetic activation and inactivation of centromeres. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
Stanca Michele A
Full Text Available Abstract Background Epigenetic phenomena have been associated with the regulation of active and silent chromatin states achieved by modifications of chromatin structure through DNA methylation, and histone post-translational modifications. The latter is accomplished, in part, through the action of PcG (Polycomb group protein complexes which methylate nucleosomal histone tails at specific sites, ultimately leading to chromatin compaction and gene silencing. Different PcG complex variants operating during different developmental stages have been described in plants. In particular, the so-called FIE/MEA/FIS2 complex governs the expression of genes important in embryo and endosperm development in Arabidopsis. In our effort to understand the epigenetic mechanisms regulating seed development in barley (Hordeum vulgare, an agronomically important monocot plant cultivated for its endosperm, we set out to characterize the genes encoding barley PcG proteins. Results Four barley PcG gene homologues, named HvFIE, HvE(Z, HvSu(z12a, and HvSu(z12b were identified and structurally and phylogenetically characterized. The corresponding genes HvFIE, HvE(Z, HvSu(z12a, and HvSu(z12b were mapped onto barley chromosomes 7H, 4H, 2H and 5H, respectively. Expression analysis of the PcG genes revealed significant differences in gene expression among tissues and seed developmental stages and between barley cultivars with varying seed size. Furthermore, HvFIE and HvE(Z gene expression was responsive to the abiotic stress-related hormone abscisic acid (ABA known to be involved in seed maturation, dormancy and germination. Conclusion This study reports the first characterization of the PcG homologues, HvFIE, HvE(Z, HvSu(z12a and HvSu(z12b in barley. All genes co-localized with known chromosomal regions responsible for malting quality related traits, suggesting that they might be used for developing molecular markers to be applied in marker assisted selection. The Pc
Full Text Available The classical idea about the function of the mammalian sperm chromatin is that it serves to transmit a highly protected and transcriptionally inactive paternal genome, largely condensed by protamines, to the next generation. In addition, recent sperm chromatin genome-wide dissection studies indicate the presence of a differential distribution of the genes and repetitive sequences in the protamine-condensed and histone-condensed sperm chromatin domains, which could be potentially involved in regulatory roles after fertilization. Interestingly, recent proteomic studies have shown that sperm chromatin contains many additional proteins, in addition to the abundant histones and protamines, with specific modifications and chromatin affinity features which are also delivered to the oocyte. Both gene and protein signatures seem to be altered in infertile patients and, as such, are consistent with the potential involvement of the sperm chromatin landscape in early embryo development. This present work reviews the available information on the composition of the human sperm chromatin and its epigenetic potential, with a particular focus on recent results derived from high-throughput genomic and proteomic studies. As a complement, we provide experimental evidence for the detection of phosphorylations and acetylations in human protamine 1 using a mass spectrometry approach. The available data indicate that the sperm chromatin is much more complex than what it was previously thought, raising the possibility that it could also serve to transmit crucial paternal epigenetic information to the embryo.
Morel, D; Almouzni, G; Soria, J-C; Postel-Vinay, S
Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors. We reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. Experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described. The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1-deficient malignant rhabdoid tumors and SMARCA4-deficient ovarian small cell carcinomas. Clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between EZH2 inhibitors and deficiencies in components of the Polycomb or SWI/SNF chromatin-remodeling complexes (including BAP1, ARID1A and PBRM1 subunits), as well as between the CREBBP and EP300 histone acetylases. Further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs. Epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly
Chromatin is the universal template of genetic information in all eukaryotic organisms. Chemical modifications of the DNA-packaging histone proteins and the DNA bases are crucial signaling events in directing the use and readout of eukaryotic genomes. The enzymes that install and remove these chromatin modifications as well as the proteins that bind these marks govern information that goes beyond the sequence of DNA. Therefore, these so-called epigenetic regulators are intensively studied and represent promising drug targets in modern medicine. We summarize and discuss recent advances in the field of chemical biology that have provided chromatin research with sophisticated tools for investigating the composition, activity, and target sites of chromatin modifying enzymes and reader proteins.
Michieletto, Davide; Marenduzzo, Davide
One of the most important problems in development is how epigenetic domains can be first established, and then maintained, within cells. To address this question, we propose a framework which couples 3D chromatin folding dynamics, to a "recolouring" process modelling the writing of epigenetic marks. Because many intra-chromatin interactions are mediated by bridging proteins, we consider a "two-state" model with self-attractive interactions between two epigenetic marks which are alike (either active or inactive). This model displays a first-order-like transition between a swollen, epigenetically disordered, phase, and a compact, epigenetically coherent, chromatin globule. If the self-attraction strength exceeds a threshold, the chromatin dynamics becomes glassy, and the corresponding interaction network freezes. By modifying the epigenetic read-write process according to more biologically-inspired assumptions, our polymer model with recolouring recapitulates the ultrasensitive response of epigenetic switches t...
Cieślik, Marcin; Bekiranov, Stefan
Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is the most widely used method for characterizing the epigenetic states of chromatin on a genomic scale. With the recent availability of large genome-wide data sets, often comprising several epigenetic marks, novel approaches are required to explore functionally relevant interactions between histone modifications. Computational discovery of "chromatin states" defined by such combinatorial interactions enabled descriptive annotations of genomes, but more quantitative approaches are needed to progress towards predictive models. We propose non-negative matrix factorization (NMF) as a new unsupervised method to discover combinatorial patterns of epigenetic marks that frequently co-occur in subsets of genomic regions. We show that this small set of combinatorial "codes" can be effectively displayed and interpreted. NMF codes enable dimensionality reduction and have desirable statistical properties for regression and classification tasks. We demonstrate the utility of codes in the quantitative prediction of Pol2-binding and the discrimination between Pol2-bound promoters and enhancers. Finally, we show that specific codes can be linked to molecular pathways and targets of pluripotency genes during differentiation. We have introduced and evaluated a new computational approach to represent combinatorial patterns of epigenetic marks as quantitative variables suitable for predictive modeling and supervised machine learning. To foster widespread adoption of this method we make it available as an open-source software-package - epicode at https://github.com/mcieslik-mctp/epicode.
Sirchia, Silvia M; Faversani, Alice; Rovina, Davide; Russo, Maria V; Paganini, Leda; Savi, Federica; Augello, Claudia; Rosso, Lorenzo; Del Gobbo, Alessandro; Tabano, Silvia; Bosari, Silvano; Miozzo, Monica
Tumor epigenetic defects are of increasing relevance to clinical practice, because they are 'druggable' targets for cancer therapy using chromatin-remodeling agents (CRAs). New evidences highlight the importance of the microenvironment on the epigenome regulation and the need to use culture models able to preserve tissue morphology, to better understand the action of CRAs. Methods & methods: We studied the epigenetic response induced by culturing and CRAs in a preclinical model, preserving ex vivo the original tissue microenvironment and morphology, assessing different epigenetic signatures. Our overall findings suggest that culturing and CRAs cause heterogeneous effects on the genes methylation; CRAs affect the global DNA methylation and can trigger an active DNA demethylation; the culture induces alterations in the histone deacetylase expression. Despite the limited number of cases, these findings can be considered a proof of concept of the possibility to test CRAs epigenetic effects on ex vivo tissues maintained in their native tissue architecture.
Gibson, Matthew D.
The eukaryotic genome is organized into a structural polymer called chromatin. Ultimately, all access to genetic information is regulated by chromatin including access required for DNA replication, transcription, and repair. The basic repeating unit of chromatin is the nucleosome which is comprised of ˜147 bp of DNA tightly wrapped around a protein histone octamer core. The histone octamer is made up of eight proteins: two each of histones H2A, H2B, H3, and H4. Many mechanisms exist to regulate access to DNA but one of pivotal importance is the creation of unique nucleosomes through i) integration of histone variants and ii) deposition of post translational modifications (PTMs). These modifications help comprise the epigenome of a cell. Classically, the two mechanisms by which they function have been through a direct regulation of nucleosome dynamics, or through third party proteins which are able to recognize the variants or PTMs and facilitate work. The library of potential PTMs therefore forms a sort of histone code which regulates access to DNA. This thesis investigates the intersection of these mechanisms to determine whether the act of recognizing epigenetic information alters DNA accessibility. The primary method used to determine changes in DNA accessibility is though observing the effective binding affinity of a transcription factor to its target site buried within a recombinantly prepared nucleosome which has been modified to carry a PTM and to report on its wrapping state. We find different regulation depending both on the PTM we investigate and the specific PTM-binding protein. We first investigate the H3K36me3-binding protein PHF1 and find that while the PTM it recognizes, H3K36me3, does not alter DNA accessibility, the binding of its recognition domain and N-terminal domain can illicit a change of DNA accessibility of 8 +/- 2-fold. This means that 8 times less DNA binding protein is required to occupy its target site if the nucleosome is bound by PHF
Braszewska-Zalewska, Agnieszka; Tylikowska, Marta; Kwasniewska, Jolanta; Szymanowska-Pulka, Joanna
In addition to their normal developmental processes, plants have evolved complex genetic and epigenetic regulatory mechanisms to cope with various environmental stresses. It has been shown that both DNA methylation and histone modifications are involved in DNA damage response to various types of stresses. In this study, we focused on the involvement of two mutagenic agents, chemical (maleic acid hydrazide; MH) and physical (gamma rays), on the global epigenetic modifications of chromatin in barley. Our results indicate that both mutagens strongly influence the level of histone methylation and acetylation. Moreover, we found that gamma irradiation, in contrast to MH, has a more robust influence on the DNA methylation level. This is the first study that brings together mutagenic treatment along with its impact at the level of epigenetic modifications examined using the immunohistochemical method.
Full Text Available In specific regions of the adult mammalian brain, neural stem cells (NSCs generate new neurons throughout life. Emerging evidence indicate that chromatin-based transcriptional regulation is a key epigenetic mechanism for the life-long function of adult NSCs. In the adult mouse brain, NSCs in the subventricular zone (SVZ retain the ability to produce both neurons and glia for the life of the animal. In this review, we discuss the origin and function of SVZ NSCs as they relate to key epigenetic concepts of development and potential underlying mechanism of chromatin-based transcriptional regulation. A central point of discussion is how SVZ NSCs – which possess many characteristics of mature, non-neurogenic astrocytes – maintain a youthful ability to produce both neuronal and glial lineages. In addition to reviewing data regarding the function of chromatin-modifying factors in SVZ neurogenesis, we incorporate our growing understanding that long noncoding RNAs (lncRNAs serve as an important element to chromatin-based transcriptional regulation, including that of SVZ NSCs. Discoveries regarding the epigenetic mechanisms of adult SVZ NSCs may provide key insights into fundamental principles of adult stem cell biology as well as the more complex and dynamic developmental environment of the embryonic brain.
Zhao, Hongying; Liu, Tingting; Liu, Ling; Zhang, Guanxiong; Pang, Lin; Yu, Fulong; Fan, Huihui; Ping, Yanyan; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia
Epigenetic modification can affect many important biological processes, such as cell proliferation and apoptosis. It can alter chromatin conformation and contribute to gene regulation. To investigate how chromatin states associated with network motifs, we assembled chromatin state-modified regulatory networks by combining 269 ChIP-seq data and chromatin states in four cell types. We found that many chromatin states were significantly associated with network motifs, especially for feedforward loops (FFLs). These distinct chromatin state compositions contribute to different expression levels and translational control of targets in FFLs. Strikingly, the chromatin state-modified FFLs were highly cell-specific and, to a large extent, determined cell-selective functions, such as the embryonic stem cell-specific bivalent modification-related FFL with an important role in poising developmentally important genes for expression. Besides, comparisons of chromatin state-modified FFLs between cancerous/stem and primary cell lines revealed specific type of chromatin state alterations that may act together with motif structural changes cooperatively contribute to cell-to-cell functional differences. Combination of these alterations could be helpful in prioritizing candidate genes. Together, this work highlights that a dynamic epigenetic dimension can help network motifs to control cell-specific functions. PMID:26169043
Michieletto, D.; Orlandini, E.; Marenduzzo, D.
One of the most important problems in development is how epigenetic domains can first be established, and then maintained, within cells. To address this question, we propose a framework that couples three-dimensional chromatin folding dynamics to a "recoloring" process modeling the writing of epigenetic marks. Because many intrachromatin interactions are mediated by bridging proteins, we consider a "two-state" model with self-attractive interactions between two epigenetic marks that are alike (either active or inactive). This model displays a first-order-like transition between a swollen, epigenetically disordered phase and a compact, epigenetically coherent chromatin globule. If the self-attraction strength exceeds a threshold, the chromatin dynamics becomes glassy, and the corresponding interaction network freezes. By modifying the epigenetic read-write process according to more biologically inspired assumptions, our polymer model with recoloring recapitulates the ultrasensitive response of epigenetic switches to perturbations and accounts for long-lived multidomain conformations, strikingly similar to the topologically associating domains observed in eukaryotic chromosomes.
Feinberg, Andrew P.; Koldobskiy, Michael A.; Göndör, Anita
This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer. PMID:26972587
Salminen, Antero; Kaarniranta, Kai; Hiltunen, Mikko; Kauppinen, Anu
Although there is a substantial literature that mitochondria have a crucial role in the aging process, the mechanism has remained elusive. The role of reactive oxygen species, mitochondrial DNA injuries, and a decline in mitochondrial quality control has been proposed. Emerging studies have demonstrated that Krebs cycle intermediates, 2-oxoglutarate (also known as α-ketoglutarate), succinate and fumarate, can regulate the level of DNA and histone methylation. Moreover, citrate, also a Krebs cycle metabolite, can enhance histone acetylation. Genome-wide screening studies have revealed that the aging process is linked to significant epigenetic changes in the chromatin landscape, e.g. global demethylation of DNA and histones and increase in histone acetylation. Interestingly, recent studies have revealed that the demethylases of DNA (TET1-3) and histone lysines (KDM2-7) are members of 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzymes are activated by oxygen, iron and the major Krebs cycle intermediate, 2-oxoglutarate, whereas they are inhibited by succinate and fumarate. Considering the endosymbiont origin of mitochondria, it is not surprising that Krebs cycle metabolites can control the gene expression of host cell by modifying the epigenetic landscape of chromatin. It seems that age-related disturbances in mitochondrial metabolism can induce epigenetic reprogramming, which promotes the appearance of senescent phenotype and degenerative diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
Turinsky, Andrei L; Turner, Brian; Borja, Rosanne C; Gleeson, James A; Heath, Michael; Pu, Shuye; Switzer, Thomas; Dong, Dong; Gong, Yunchen; On, Tuan; Xiong, Xuejian; Emili, Andrew; Greenblatt, Jack; Parkinson, John; Zhang, Zhaolei; Wodak, Shoshana J
Chromatin modification (CM) is a set of epigenetic processes that govern many aspects of DNA replication, transcription and repair. CM is carried out by groups of physically interacting proteins, and their disruption has been linked to a number of complex human diseases. CM remains largely unexplored, however, especially in higher eukaryotes such as human. Here we present the DAnCER resource, which integrates information on genes with CM function from five model organisms, including human. Currently integrated are gene functional annotations, Pfam domain architecture, protein interaction networks and associated human diseases. Additional supporting evidence includes orthology relationships across organisms, membership in protein complexes, and information on protein 3D structure. These data are available for 962 experimentally confirmed and manually curated CM genes and for over 5000 genes with predicted CM function on the basis of orthology and domain composition. DAnCER allows visual explorations of the integrated data and flexible query capabilities using a variety of data filters. In particular, disease information and functional annotations are mapped onto the protein interaction networks, enabling the user to formulate new hypotheses on the function and disease associations of a given gene based on those of its interaction partners. DAnCER is freely available at http://wodaklab.org/dancer/.
Zucconi, Beth E; Cole, Philip A
Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings. Copyright © 2017 Elsevier Ltd. All rights reserved.
Sundar, Isaac K; Rahman, Irfan
Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and histones, and for modulation of gene expression patterns in response to cigarette smoke (CS), are not known. We hypothesize that CS exposure alters the gene expression patterns of chromatin-modifying enzymes, which then affects multiple downstream pathways involved in the response to CS. We have, therefore, analyzed chromatin-modifying enzyme profiles and validated by quantitative real-time PCR (qPCR). We also performed immunoblot analysis of targeted histone marks in C57BL/6J mice exposed to acute and subchronic CS, and of lungs from nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). We found a significant increase in expression of several chromatin modification enzymes, including DNA methyltransferases, histone acetyltransferases, histone methyltransferases, and SET domain proteins, histone kinases, and ubiquitinases. Our qPCR validation data revealed a significant downregulation of Dnmt1, Dnmt3a, Dnmt3b, Hdac2, Hdac4, Hat1, Prmt1, and Aurkb We identified targeted chromatin histone marks (H3K56ac and H4K12ac), which are induced by CS. Thus CS-induced genotoxic stress differentially affects the expression of epigenetic modulators that regulate transcription of target genes via DNA methylation and site-specific histone modifications. This may have implications in devising epigenetic-based therapies for COPD and lung cancer. Copyright © 2016 the American Physiological Society.
Sharma, Santosh Kumar; Yamamoto, Maki; Mukai, Yasuhiko
Histone proteins and the nucleosomes along with DNA are the essential components of eukaryotic chromatin. Post-translational histone-DNA interactions and modifications eventually offer significant alteration in the chromatin environment and potentially influence diverse fundamental biological processes, some of which are known to be epigenetically inherited and constitute the "epigenetic code". Such chromatin modifications evidently uncover remarkable diversity and biological specificity associated with distinct patterns of covalent histone marks. The past few years have witnessed major breakthroughs in plant biology research by utilizing chromatin modification-specific antibodies through molecular cytogenetic tools to ascertain hallmark signatures of chromatin domains on the chromosomes. Here, we survey current information on chromosomal distribution patterns of chromatin modifications with special emphasis on histone methylation, acetylation, phosphorylation, and centromere-specific histone 3 (CENH3) marks in plants using immuno-FISH as a basic tool. Major available information has been classified under typical and comparative cytogenetic detection of chromatin modifications in plants. Further, spatial distribution of chromatin environment that exists between different cell types such as angiosperm/gymnosperm, monocot/dicot, diploid/polyploids, vegetative/generative cells, as well as different stages, i.e., mitosis versus meiosis has also been discussed in detail. Several challenges and future perspectives of molecular cytogenetics in the grooming field of plant chromatin dynamics have also been addressed.
Boettiger, Alistair N; Bintu, Bogdan; Moffitt, Jeffrey R; Wang, Siyuan; Beliveau, Brian J; Fudenberg, Geoffrey; Imakaev, Maxim; Mirny, Leonid A; Wu, Chao-ting; Zhuang, Xiaowei
Metazoan genomes are spatially organized at multiple scales, from packaging of DNA around individual nucleosomes to segregation of whole chromosomes into distinct territories. At the intermediate scale of kilobases to megabases, which encompasses the sizes of genes, gene clusters and regulatory domains, the three-dimensional (3D) organization of DNA is implicated in multiple gene regulatory mechanisms, but understanding this organization remains a challenge. At this scale, the genome is partitioned into domains of different epigenetic states that are essential for regulating gene expression. Here we investigate the 3D organization of chromatin in different epigenetic states using super-resolution imaging. We classified genomic domains in Drosophila cells into transcriptionally active, inactive or Polycomb-repressed states, and observed distinct chromatin organizations for each state. All three types of chromatin domains exhibit power-law scaling between their physical sizes in 3D and their domain lengths, but each type has a distinct scaling exponent. Polycomb-repressed domains show the densest packing and most intriguing chromatin folding behaviour, in which chromatin packing density increases with domain length. Distinct from the self-similar organization displayed by transcriptionally active and inactive chromatin, the Polycomb-repressed domains are characterized by a high degree of chromatin intermixing within the domain. Moreover, compared to inactive domains, Polycomb-repressed domains spatially exclude neighbouring active chromatin to a much stronger degree. Computational modelling and knockdown experiments suggest that reversible chromatin interactions mediated by Polycomb-group proteins play an important role in these unique packaging properties of the repressed chromatin. Taken together, our super-resolution images reveal distinct chromatin packaging for different epigenetic states at the kilobase-to-megabase scale, a length scale that is directly
The nuclear sub- structure which provides a skeletal framework for periodic attachment of the 30nm chromatin fiber to form loop structures has been termed as the .... Various features of the human genome that transcend its primary. DNA sequence, such as chromatin packaging, his- tone modifications, and DNA methylation ...
Aguilar, Carlos A.; Craighead, Harold G.
Deoxyribonucleic acid (DNA) is the blueprint on which life is based and transmitted, but the way in which chromatin -- a dynamic complex of nucleic acids and proteins -- is packaged and behaves in the cellular nucleus has only begun to be investigated. Epigenetic modifications sit 'on top of' the genome and affect how DNA is compacted into chromatin and transcribed into ribonucleic acid (RNA). The packaging and modifications around the genome have been shown to exert significant influence on cellular behaviour and, in turn, human development and disease. However, conventional techniques for studying epigenetic or conformational modifications of chromosomes have inherent limitations and, therefore, new methods based on micro- and nanoscale devices have been sought. Here, we review the development of these devices and explore their use in the study of DNA modifications, chromatin modifications and higher-order chromatin structures.
Full Text Available Chromatin contains valuable epigenetic information comprising of both DNA and post translational histone modifications. Traditionally, detection of epigenetic modifications on DNA and histone proteins requires different and elaborate preparation steps. In this study we report on a facile and unique approach for the simultaneous detection and quantification of epigenetic modifications on DNA and histone proteins in one sample preparation step. Our novel one-pot technique consists of a chromatin extraction step from whole blood using bi-functional carboxyl-functionalized magnetic nanoparticles as solid-phase absorbents. Leucocytes enrichment from blood and chromatin extracted from the leucocytes by lysis was achieved with the same carboxyl-functionalized magnetic nanoparticles. The isolated chromatin was then eluted from the magnetic nanoparticles with PBS 1×. Using the eluted chromatin as substrate, we developed a quantitative method for simultaneous detection of epigenetic modifications on DNA and histone proteins by a biotin–streptavidin mediated enzyme-based immunosorbent assay (two-step EIA on a 96-well plate. The simultaneous detection of epigenetic modifications on DNA and histone was validated by DNA-based EIA and histone-based Western blotting analysis performed separately with conventional protocols. By coupling cell separation and chromatin purification with a simple detection module, the global epigenetic information could be evaluated in less than 8 h in leucocytes from blood. Our simplified cross-platform approach can be used by most laboratories for multiplex detection, uses non-hazardous materials and could be integrated with microfabrication methods for onchip analysis.
The specialized cell types of tissues and organs are generated during development and are replenished over lifetime though the process of differentiation. During differentiation the characteristics and identity of cells are changed to meet their functional requirements. Differentiated cells then faithfully maintain their characteristic gene expression patterns. On the molecular level transcription factors have a key role in instructing specific gene expression programs. They act together with chromatin regulators which stabilize expression patterns. Current evidence indicates that epigenetic mechanisms are essential for maintaining stable cell identities. Conversely, the disruption of chromatin regulators is associated with disease and cellular transformation. In mammals, a large number of chromatin regulators have been identified. The Polycomb group complexes and the DNA methylation system have been widely studied in development. Other chromatin regulators remain to be explored. This chapter focuses on recent advances in understanding epigenetic regulation in embryonic and adult stem cells in mammals. The available data illustrate that several chromatin regulators control key lineage specific genes. Different epigenetic systems potentially could provide stability and guard against loss or mutation of individual components. Recent experiments also suggest intervals in cell differentiation and development when new epigenetic patterns are established. Epigenetic patterns have been observed to change at a progenitor state after stem cells commit to differentiation. This finding is consistent with a role of epigenetic regulation in stabilizing expression patterns after their establishment by transcription factors. However, the available data also suggest that additional, presently unidentified, chromatin regulatory mechanisms exist. Identification of these mechanism is an important aim for future research to obtain a more complete framework for understanding stem cell
Full Text Available Epigenetic regulation can be altered by environmental cues including abiotic and biotic stresses. In most cases, environmentally-induced epigenetic changes are transient, but in some cases they are maintained for extensive periods of time and may even be transmitted to the next generation. However, the underlying mechanisms of transgenerational transmission of environmentally-induced epigenetic states remain largely unknown. Such traits can be adaptive, but also can have negative consequences if the parentally inherited epigenetic memory interferes with canonical environmental responses of the progeny. This review highlights recent insights into the mechanisms preventing transgenerational transmission of environmentally-induced epigenetic states in plants, which resemble those of germline reprogramming in mammals.
Tropberger, Philipp; Mercier, Alexandre; Robinson, Margaret; Zhong, Weidong; Ganem, Don E.; Holdorf, Meghan
Chronic hepatitis B virus (HBV) infection affects 240 million people worldwide and is a major risk factor for liver failure and hepatocellular carcinoma. Current antiviral therapy inhibits cytoplasmic HBV genomic replication, but is not curative because it does not directly affect nuclear HBV closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target cccDNA regulation would therefore be highly desirable. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications (PTMs). Here, using a new cccDNA ChIP-Seq approach, we report, to our knowledge, the first genome-wide maps of PTMs in cccDNA-containing chromatin from de novo infected HepG2 cells, primary human hepatocytes, and from HBV-infected liver tissue. We find high levels of PTMs associated with active transcription enriched at specific sites within the HBV genome and, surprisingly, very low levels of PTMs linked to transcriptional repression even at silent HBV promoters. We show that transcription and active PTMs in HBV chromatin are reduced by the activation of an innate immunity pathway, and that this effect can be recapitulated with a small molecule epigenetic modifying agent, opening the possibility that chromatin-based regulation of cccDNA transcription could be a new therapeutic approach to chronic HBV infection. PMID:26438841
Full Text Available Epigenetics deals with the interactions between genes and the immediate cellular environment. These interactions go a long way in shaping up each and every person’s individuality. Further, reversibility of epigenetic interactions may offer a dynamic control over the expression of various critical genes. Thus, tweaking the epigenetic machinery may help cause or cure diseases, especially cancer. Therefore, cancer epigenetics, especially at a molecular level, needs to be scrutinised closely, as it could potentially serve as the future pharmaceutical goldmine against neoplastic diseases. However, in view of its rapidly enlarging scope of application, it has become difficult to keep abreast of scientific information coming out of various epigenetic studies directed against cancer. Using this review, we have attempted to shed light on two of the most important mechanisms implicated in cancer, that is, DNA (deoxyribonucleic acid methylation and histone modifications, and their place in cancer pathogenesis. Further, we have attempted to take stock of the new epigenetic drugs that have emerged onto the market as well as those in the pipeline that offer hope in mankind’s fight against cancer.
Haladyna, Jessica N; Yamauchi, Taylor; Neff, Tobias; Bernt, Kathrin M
Genome scale sequencing in patients with cancer has revealed a lower frequency of genetic aberrations in hematologic disorders compared with most other malignancies, suggesting a prominent role for epigenetic mechanisms. In parallel, epigenetic modifiers that are altered in cancer play critical roles in normal hematopoietic development, influencing both self-renewal of hematopoietic stem cells and differentiation into the different lineages. In this review, we aim to compare the role of several key DNA or histone modifying enzymes and complexes in normal development and hematopoietic malignancies, including DNMT3A, TET2, IDH1, IDH2, MLL1, MLL4, DOT1L, PRC1/2 and WSHC1/NSD2/MMSET. Insights into their biological mechanisms led to the development of therapies designed to target mutant IDH1 and IDH2, DOT1L in MLL-rearranged leukemias and EZH2 in several cancer types including lymphomas. Inhibitors for these enzymes are currently in clinical trials.
Persson, Jenna [Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet (Sweden); Ekwall, Karl, E-mail: email@example.com [Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet (Sweden); School of Life Sciences, University College Sodertorn, NOVUM, Huddinge (Sweden)
Eukaryotic DNA is packaged around octamers of histone proteins into nucleosomes, the basic unit of chromatin. In addition to enabling meters of DNA to fit within the confines of a nucleus, the structure of chromatin has functional implications for cell identity. Covalent chemical modifications to the DNA and to histones, histone variants, ATP-dependent chromatin remodelers, small noncoding RNAs and the level of chromatin compaction all contribute to chromosomal structure and to the activity or silencing of genes. These chromatin-level alterations are defined as epigenetic when they are heritable from mother to daughter cell. The great diversity of epigenomes that can arise from a single genome permits a single, totipotent cell to generate the hundreds of distinct cell types found in humans. Two recent studies in mouse and in fly have highlighted the importance of Chd1 chromatin remodelers for maintaining an open, active chromatin state. Based on evidence from fission yeast as a model system, we speculate that Chd1 remodelers are involved in the disassembly of nucleosomes at promoter regions, thus promoting active transcription and open chromatin. It is likely that these nucleosomes are specifically marked for disassembly by the histone variant H2A.Z.
There is growing experimental evidence from both animals and plants that changes in the environment can have profound effects on the epigenetic state of chromatin in nuclei. The epigenetic state of chromatin and the cell-specific transcription profile of genes are mitotically stable and, sometimes, can be transmitted across generations. Plants often show stable transgenerational inheritance of induced alterations of epigenetic states that are associated with morphologically or physiologically distinctive phenotypes. This pattern of inheritance may be due to the fact that germ cells produced by terminal differentiation and to the absence of appreciable epigenetic reprogramming during the life cycle. Recent advances in mass sequencing technology have accelerated the decoding of the epigenomes of various tissues and cell types and provided new insights into the dynamics of epigenetic changes during the plant life cycle and in response to environmental challenges. As plants have a sessile nature, the epigenetic regulation of genes and transposable elements in response to environmental stresses might be crucial for the generation and inheritance of phenotypic variations in plants in natural populations.
Ordog, Tamas; Syed, Sabriya; Hayashi, Yujiro; Asuzu, David T.
Background Motility and functional gastrointestinal disorders have high prevalence in the community, cause significant morbidity and represent a major health care burden. Despite major advances in our understanding of the cellular and molecular basis of gastrointestinal neuromuscular functions, many of these diseases still defy mechanistic explanations. The biopsychosocial model underlying the current classification of functional gastrointestinal disorders recognizes and integrates the pathogenetic role of genetic, environmental and psychosocial factors but has not been associated with specific molecular mechanisms. Purpose Here we propose that this integrative function is encoded in the chromatin composed of the DNA and associated histone and nonhistone proteins and noncoding RNA. By establishing epigenetically heritable “molecular memories” of past stimuli including environmental challenges, the chromatin determines an individual’s responses to future insults and translates them into high-order outputs such as symptoms and illness behavior. Thus, surveying epigenetic signatures throughout the genome of affected cells in individual patients may make it possible to better understand and ultimately control the phenomena described by the biopsychosocial model. In this review we provide a high-level but comprehensive description of the concepts and mechanisms underlying epigenetics and chromatin dynamics, describe the mechanisms whereby the environment can alter the epigenome and identify aspects of functional gastrointestinal and motility disorders where epigenetic mechanisms are most likely to play important roles. PMID:23095056
Singh Nanda, Jagpreet; Kumar, Rahul; Raghava, Gajendra P S
We have developed a database called dbEM (database of Epigenetic Modifiers) to maintain the genomic information of about 167 epigenetic modifiers/proteins, which are considered as potential cancer targets. In dbEM, modifiers are classified on functional basis and comprise of 48 histone methyl transferases, 33 chromatin remodelers and 31 histone demethylases. dbEM maintains the genomic information like mutations, copy number variation and gene expression in thousands of tumor samples, cancer cell lines and healthy samples. This information is obtained from public resources viz. COSMIC, CCLE and 1000-genome project. Gene essentiality data retrieved from COLT database further highlights the importance of various epigenetic proteins for cancer survival. We have also reported the sequence profiles, tertiary structures and post-translational modifications of these epigenetic proteins in cancer. It also contains information of 54 drug molecules against different epigenetic proteins. A wide range of tools have been integrated in dbEM e.g. Search, BLAST, Alignment and Profile based prediction. In our analysis, we found that epigenetic proteins DNMT3A, HDAC2, KDM6A, and TET2 are highly mutated in variety of cancers. We are confident that dbEM will be very useful in cancer research particularly in the field of epigenetic proteins based cancer therapeutics. This database is available for public at URL: http://crdd.osdd.net/raghava/dbem.
Singh Nanda, Jagpreet; Kumar, Rahul; Raghava, Gajendra P. S.
We have developed a database called dbEM (database of Epigenetic Modifiers) to maintain the genomic information of about 167 epigenetic modifiers/proteins, which are considered as potential cancer targets. In dbEM, modifiers are classified on functional basis and comprise of 48 histone methyl transferases, 33 chromatin remodelers and 31 histone demethylases. dbEM maintains the genomic information like mutations, copy number variation and gene expression in thousands of tumor samples, cancer cell lines and healthy samples. This information is obtained from public resources viz. COSMIC, CCLE and 1000-genome project. Gene essentiality data retrieved from COLT database further highlights the importance of various epigenetic proteins for cancer survival. We have also reported the sequence profiles, tertiary structures and post-translational modifications of these epigenetic proteins in cancer. It also contains information of 54 drug molecules against different epigenetic proteins. A wide range of tools have been integrated in dbEM e.g. Search, BLAST, Alignment and Profile based prediction. In our analysis, we found that epigenetic proteins DNMT3A, HDAC2, KDM6A, and TET2 are highly mutated in variety of cancers. We are confident that dbEM will be very useful in cancer research particularly in the field of epigenetic proteins based cancer therapeutics. This database is available for public at URL: http://crdd.osdd.net/raghava/dbem.
Lämke, Jörn; Bäurle, Isabel
Plants frequently have to weather both biotic and abiotic stressors, and have evolved sophisticated adaptation and defense mechanisms. In recent years, chromatin modifications, nucleosome positioning, and DNA methylation have been recognized as important components in these adaptations. Given their potential epigenetic nature, such modifications may provide a mechanistic basis for a stress memory, enabling plants to respond more efficiently to recurring stress or even to prepare their offspring for potential future assaults. In this review, we discuss both the involvement of chromatin in stress responses and the current evidence on somatic, intergenerational, and transgenerational stress memory.
Setiaputra, Dheva T; Yip, Calvin K
Eukaryotic cells package their genome in the form of a DNA-protein complex known as chromatin. This organization not only condenses the genome to fit within the confines of the nucleus, but also provides a platform for a cell to regulate accessibility to different gene sequences. The basic packaging element of chromatin is the nucleosome, which consists of 146 base pairs of DNA wrapped around histone proteins. One major means that a cell regulates chromatin structure is by depositing post-translational modifications on nucleosomal histone proteins, and thereby altering internucleosomal interactions and/or binding to different chromatin associated factors. These chromatin modifications are often catalyzed by multi-subunit enzyme complexes, whose large size, sophisticated composition, and inherent conformational flexibility pose significant technical challenges to their biochemical and structural characterization. Multiple structural approaches including nuclear magnetic resonance spectroscopy, X-ray crystallography, single-particle electron microscopy, and crosslinking coupled to mass spectrometry are often used synergistically to probe the overall architecture, subunit organization, and catalytic mechanisms of these macromolecular assemblies. In this review, we highlight several recent chromatin-modifying complexes studies that embodies this multipronged structural approach, and explore common themes amongst them. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. Copyright © 2017 Elsevier B.V. All rights reserved.
Kim, Jung-Hyun; Ebersole, Thomas; Kouprina, Natalay; Noskov, Vladimir N; Ohzeki, Jun-Ichirou; Masumoto, Hiroshi; Mravinac, Brankica; Sullivan, Beth A; Pavlicek, Adam; Dovat, Sinisa; Pack, Svetlana D; Kwon, Yoo-Wook; Flanagan, Patrick T; Loukinov, Dmitri; Lobanenkov, Victor; Larionov, Vladimir
The role of repetitive DNA sequences in pericentromeric regions with respect to kinetochore/heterochromatin structure and function is poorly understood. Here, we use a mouse erythroleukemia cell (MEL) system for studying how repetitive DNA assumes or is assembled into different chromatin structures. We show that human gamma-satellite DNA arrays allow a transcriptionally permissive chromatin conformation in an adjacent transgene and efficiently protect it from epigenetic silencing. These arrays contain CTCF and Ikaros binding sites. In MEL cells, this gamma-satellite DNA activity depends on binding of Ikaros proteins involved in differentiation along the hematopoietic pathway. Given our discovery of gamma-satellite DNA in pericentromeric regions of most human chromosomes and a dynamic chromatin state of gamma-satellite arrays in their natural location, we suggest that gamma-satellite DNA represents a unique region of the functional centromere with a possible role in preventing heterochromatin spreading beyond the pericentromeric region.
Lodhi, Niraj; Kossenkov, Andrew V; Tulin, Alexei V
Epigenetics are the heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. After mitosis, it is thought that bookmarking transcription factors remain at promoters, regulating which genes become active and which remain silent. Herein, we demonstrate that poly(ADP-ribose)polymerase-1 (PARP-1) is a genome-wide epigenetic memory mark in mitotic chromatin, and we further show that the presence of PARP-1 is absolutely crucial for reactivation of transcription after mitosis. Based on these findings, a novel molecular model of epigenetic memory transmission through the cell cycle is proposed. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
Vijayalakshmi H Nagaraj
Full Text Available In addition to gene network switches, local epigenetic modifications to DNA and histones play an important role in all-or-none cellular decision-making. Here, we study the dynamical design of a well-characterized epigenetic chromatin switch: the yeast SIR system, in order to understand the origin of the stability of epigenetic states. We study hysteresis in this system by perturbing it with a histone deacetylase inhibitor. We find that SIR silencing has many characteristics of a non-linear bistable system, as observed in conventional genetic switches, which are based on activities of a few promoters affecting each other through the abundance of their gene products. Quite remarkably, our experiments in yeast telomeric silencing show a very distinctive pattern when it comes to the transition from bistability to monostability. In particular, the loss of the stable silenced state, upon increasing the inhibitor concentration, does not seem to show the expected saddle node behavior, instead looking like a supercritical pitchfork bifurcation. In other words, the 'off' state merges with the 'on' state at a threshold concentration leading to a single state, as opposed to the two states remaining distinct up to the threshold and exhibiting a discontinuous jump from the 'off' to the 'on' state. We argue that this is an inevitable consequence of silenced and active regions coexisting with dynamic domain boundaries. The experimental observations in our study therefore have broad implications for the understanding of chromatin silencing in yeast and beyond.
Full Text Available Mature B-cell lymphoma is a clinically and biologically highly diverse disease. Its diagnosis and prognosis is a challenge due to its molecular heterogeneity and diverse regimes of biological dysfunctions, which are partly driven by epigenetic mechanisms. We here present an integrative analysis of DNA methylation and gene expression data of several lymphoma subtypes. Our study confirms previous results about the role of stemness genes during development and maturation of B-cells and their dysfunction in lymphoma locking in more proliferative or immune-reactive states referring to B-cell functionalities in the dark and light zone of the germinal center and also in plasma cells. These dysfunctions are governed by widespread epigenetic effects altering the promoter methylation of the involved genes, their activity status as moderated by histone modifications and also by chromatin remodeling. We identified four groups of genes showing characteristic expression and methylation signatures among Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma and multiple myeloma. These signatures are associated with epigenetic effects such as remodeling from transcriptionally inactive into active chromatin states, differential promoter methylation and the enrichment of targets of transcription factors such as EZH2 and SUZ12.
Wary, Anita; Wary, Neil; Baruah, Jugajyoti; Mastej, Victoria; Wary, Kishore K
The human epigenome is plastic. The goal of this study was to address if fibroblast cells can be epigenetically modified to promote neovessel formation. Here, we used highly abundant human adult dermal fibroblast cells (hADFCs) that were treated with the chromatin-modifying agents 5-aza-2'-deoxycytidine and trichostatin A, and subsequently subjected to differentiation by activating Wnt signaling. Our results show that these epigenetically modified hADFCs increasingly expressed β-catenin, pluripotency factor octamer-binding transcription factor-4 (OCT4, also known as POU5F1), and endothelial cell (EC) marker called vascular endothelial growth factor receptor-2 (VEGFR-2, also known as Fetal Liver Kinase-1). In microscopic analysis, β-catenin localized to cell-cell contact points, while OCT4 was found to be localized primarily to the nucleus of these cells. Furthermore, in a chromatin immunoprecipitation experiment, OCT4 bound to the VEGFR-2/FLK1 promoter. Finally, these modified hADFCs also transduced Wnt signaling. Importantly, on a two-dimensional (2D) gel substrate, a subset of the converted cells formed vascular network-like structures in the presence of VEGF. Chromatin-modifying agents converted hADFCs to OCT4+ and VEGFR-2+ capillary tube-forming cells in a 2D matrix in VEGF-dependent manner.
Anderly C Chueh
Full Text Available We have previously identified and characterized the phenomenon of ectopic human centromeres, known as neocentromeres. Human neocentromeres form epigenetically at euchromatic chromosomal sites and are structurally and functionally similar to normal human centromeres. Recent studies have indicated that neocentromere formation provides a major mechanism for centromere repositioning, karyotype evolution, and speciation. Using a marker chromosome mardel(10 containing a neocentromere formed at the normal chromosomal 10q25 region, we have previously mapped a 330-kb CENP-A-binding domain and described an increased prevalence of L1 retrotransposons in the underlying DNA sequences of the CENP-A-binding clusters. Here, we investigated the potential role of the L1 retrotransposons in the regulation of neocentromere activity. Determination of the transcriptional activity of a panel of full-length L1s (FL-L1s across a 6-Mb region spanning the 10q25 neocentromere chromatin identified one of the FL-L1 retrotransposons, designated FL-L1b and residing centrally within the CENP-A-binding clusters, to be transcriptionally active. We demonstrated the direct incorporation of the FL-L1b RNA transcripts into the CENP-A-associated chromatin. RNAi-mediated knockdown of the FL-L1b RNA transcripts led to a reduction in CENP-A binding and an impaired mitotic function of the 10q25 neocentromere. These results indicate that LINE retrotransposon RNA is a previously undescribed essential structural and functional component of the neocentromeric chromatin and that retrotransposable elements may serve as a critical epigenetic determinant in the chromatin remodelling events leading to neocentromere formation.
Motwani, Tina; Poddar, Minakshi; Holmes, Scott G
Epigenetic mechanisms maintain the specific characteristics of differentiated cells by ensuring the inheritance of gene expression patterns through DNA replication and mitosis. We examined the mechanism of epigenetic inheritance of Sir protein-dependent transcriptional silencing in Saccharomyces cerevisiae by examining gene expression and molecular markers of silencing at the silent mating type loci under conditions of limiting Sir3 protein. We observed that silencing at HMR, as previously reported for HML, is epigenetically inherited. This inheritance is accompanied by an increased ability of previously silenced cells to retain or recruit limiting Sir3 protein to cis-acting silencer sequences. We also observed that the low H4-K16 histone acetylation and H3-K79 methylation associated with a silenced HMR locus persist in recently derepressed cells for several generations at levels of Sir3 insufficient to maintain these marks in long-term-derepressed cells. The unique ability of previously silenced cells to retain Sir3 protein, maintain silencing-specific histone modifications, and repress HMR transcription at levels of Sir3 insufficient to mediate these effects in long-term-derepressed cells suggests that a cis-acting, chromatin-based mechanism drives epigenetic inheritance at this locus.
Li, Jun; Duns, Gerben; Westers, Helga; Sijmons, Rolf; van den Berg, Anke; Kok, Klaas
In the past decade important progress has been made in our understanding of the epigenetic regulatory machinery. It has become clear that genetic aberrations in multiple epigenetic modifier proteins are associated with various types of cancer. Moreover, targeting the epigenome has emerged as a novel
Fu, Qi; Yu, Xing; Callaway, Christopher W; Lane, Robert H; McKnight, Robert A
Intrauterine growth restriction (IUGR) decreases serum insulin growth factor-1 (IGF-1) levels. IGF-1 is an epigenetically regulated gene that has two promoters, alternative exon 5 splicing, and multiple termination sites. The regulation of gene expression involves the whole gene, as evidenced by the aforementioned IGF-1 paradigm. We hypothesized that IUGR in the rat would affect hepatic IGF-1 expression and alter the epigenetic characteristics of the IGF-1 gene along its length. IUGR was induced through a bilateral uterine artery ligation of the pregnant rat, a well-characterized model of IUGR. Pups from anesthesia and sham-operated dams were used as controls. Real-time RT-PCR and ELISA was used to measure expression at day of life (DOL) 0 and 21. Bisulfite sequencing and chromatin immunoprecipitation (ChIP) quantified IGF-1 epigenetic characteristics. A nontranscribed intergenic control was used for ChIP studies. IUGR decreased hepatic and serum IGF-1. Concurrently, IUGR modified epigenetic characteristics, particularly the histone code, along the length of the hepatic IGF-1 gene. Many changes persisted postnatally, and the postnatal effect of IUGR on the histone code was gender-specific. We conclude that IUGR modifies epigenetic characteristics of the rat hepatic IGF-1 gene along the length of the whole gene.
Pikaard, Craig S; Mittelsten Scheid, Ortrun
The study of epigenetics in plants has a long and rich history, from initial descriptions of non-Mendelian gene behaviors to seminal discoveries of chromatin-modifying proteins and RNAs that mediate...
Lawaetz, Andreas C.; Almstrup, Kristian
Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS...... cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement...... of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men....
Full Text Available Abstract Background During early mouse development, two extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE and the primitive endoderm (PrE. Epigenetic changes known to take place during these early stages include changes in DNA methylation and modified histones, as well as dynamic changes in gene expression. Results In order to understand the role and extent of chromatin-based changes for lineage commitment within the embryo, we examined the epigenetic profiles of mouse embryonic stem (ES, trophectoderm stem (TS and extra-embryonic endoderm (XEN stem cell lines that were derived from the inner cell mass (ICM, TE and PrE, respectively. As an initial indicator of the chromatin state, we assessed the replication timing of a cohort of genes in each cell type, based on data that expressed genes and acetylated chromatin domains, generally, replicate early in S-phase, whereas some silent genes, hypoacetylated or condensed chromatin tend to replicate later. We found that many lineage-specific genes replicate early in ES, TS and XEN cells, which was consistent with a broadly 'accessible' chromatin that was reported previously for multiple ES cell lines. Close inspection of these profiles revealed differences between ES, TS and XEN cells that were consistent with their differing lineage affiliations and developmental potential. A comparative analysis of modified histones at the promoters of individual genes showed that in TS and ES cells many lineage-specific regulator genes are co-marked with modifications associated with active (H4ac, H3K4me2, H3K9ac and repressive (H3K27me3 chromatin. However, in XEN cells several of these genes were marked solely by repressive modifications (such as H3K27me3, H4K20me3. Consistent with TS and XEN having a restricted developmental potential, we show that these cells selectively reprogramme somatic cells to induce the de novo expression of genes associated with extraembryonic differentiation
Morgan, William F; Kovalchuk, Olga; Dolinoy, Dana C; Dubrova, Yuri E; Coleman, Matthew A; Schär, Primo; Pogribny, Igor; Hendzel, Michael
The Low Dose Radiation Symposium thoughtfully addressed ionizing radiation non-mutational but transmissable alterations in surviving cells. Deregulation of epigenetic processes has been strongly implicated in carcinogenesis, and there is increasing realization that a significant fraction of non-targeted and adaptive mechanisms in response to ionizing radiation are likely to be epigenetic in nature. Much remains to be learned about how chromatin and epigenetic regulators affect responses to low doses of radiation, and how low dose radiation impacts other epigenetic processes. The Epigenetic Mechanisms Symposium focused on on epigenetic mechanisms and their interplay with DNA repair and chromatin changes. Addressing the fact that the most well understood mediators of epigenetic regulation are histone modifications and DNA methylation. Low levels of radiation can lead to changes in the methylation status of certain gene promoters and the expression of DNA methyltransferases, However, epigenetic regulation can also involve changes in higher order chromosome structure.
Hendriks, Ivo A; Treffers, Louise W; Verlaan-de Vries, Matty
Small ubiquitin-like modifiers play critical roles in the DNA damage response (DDR). To increase our understanding of SUMOylation in the mammalian DDR, we employed a quantitative proteomics approach in order to identify dynamically regulated SUMO-2 conjugates and modification sites upon treatment...... with the DNA damaging agent methyl methanesulfonate (MMS). We have uncovered a dynamic set of 20 upregulated and 33 downregulated SUMO-2 conjugates, and 755 SUMO-2 sites, of which 362 were dynamic in response to MMS. In contrast to yeast, where a response is centered on homologous recombination, we identified......-targeted ubiquitin ligase RNF4 and degraded by the proteasome in response to DNA damage, JARID1C was SUMOylated and recruited to the chromatin to demethylate histone H3K4....
Thomas, Nicholas J.; Stevick, Rebecca J.; Tran, Luan H.; Nalavadi, Mohit O.; Almeida, Eduardo A.C.; Globus, Ruth K.; Alwood, Joshua S.
Little is known about the effects of spaceflight conditions on epigenetics. The term epigenetics describes changes to the genome that can affect expression of a gene without changes to the sequence of DNA. Epigenetic processes are thought to underlie cellular differentiation, where transcription of specific genes occurs in response to key stimuli, and may be heritable - passing from one cell to its daughter cell. We hypothesize that the mechanical environment during spaceflight, namely microgravity-induced weightlessness or exercise regulate gene expression in the osteoblast-lineage cells both to control bone formation by osteoblasts and bone resorption by osteoclasts, which continually shapes bone structure throughout life. Similarly we intend to evaluate how radiation regulates these same bone cell activity and differentiation related genes. We further hypothesize that the regulation in bone cell gene expression is at least partially controlled through epigenetic mechanisms of methylation or small non-coding RNA (microRNAs). We have acquired preliminary data suggesting that global genome methylation is modified in response to axial compression of the tibia - a model of exercise. We intend to pursue these hypotheses wherein we will evaluate changes in gene expression and, congruently, changes in epigenetic state in bones from mice subjected to the aforementioned conditions: hindlimb unloading to simulate weightlessness, axial compression of the tibia, or radiation exposure in order to gain insight into the role of epigenetics in spaceflight-induced bone loss.
Barrett, Ruth M.; Wood, Marcelo A.
One of the alluring aspects of examining chromatin modifications in the role of modulating transcription required for long-term memory processes is that these modifications may provide transient and potentially stable epigenetic marks in the service of activating and/or maintaining transcriptional processes. These, in turn, may ultimately…
Aumann, Shlomzion; Abdel-Wahab, Omar
Genomic discovery efforts in patients with cancer have been critical in identifying a recurrent theme of mutations in epigenetic modifiers. A number of novel and exciting basic biological findings have come from this work including the discovery of an enzymatic pathway for DNA cytosine demethylation, a link between cancer metabolism and epigenetics, and the critical importance of post-translational modifications at specific histone residues in malignant transformation. Identification of cancer cell dependency on a number of these mutations has quickly resulted in the development of therapies targeting several of these genetic alterations. This includes, the development of mutant-selective IDH1 and IDH2 inhibitors, DOT1L inhibitors for MLL rearranged leukemias, EZH2 inhibitors for several cancer types, and the development of bromodomain inhibitors for many cancer types--all of which are in early phase clinical trials. In many cases, however, specific genetic targets linked to malignant transformation following mutations in individual epigenetic modifiers are not yet known. In this review we present functional evidence of how alterations in frequently mutated epigenetic modifiers promote malignant transformation and how these alterations are being targeted for cancer therapeutics. Copyright © 2014 Elsevier Inc. All rights reserved.
Shankar, Eswar; Kanwal, Rajnee; Candamo, Mario; Gupta, Sanjay
The influence of diet and environment on human health has been known since ages. Plant-derived natural bioactive compounds (phytochemicals) have acquired an important role in human diet as potent antioxidants and cancer chemopreventive agents. In past few decades, the role of epigenetic alterations such as DNA methylation, histone modifications and non-coding RNAs in the regulation of mammalian genome have been comprehensively addressed. Although the effects of dietary phytochemicals on gene expression and signaling pathways have been widely studied in cancer, the impact of these dietary compounds on mammalian epigenome is rapidly emerging. The present review outlines the role of different epigenetic mechanisms in the regulation and maintenance of mammalian genome and focuses on the role of dietary phytochemicals as epigenetic modifiers in cancer. Above all, the review focuses on summarizing the progress made thus far in cancer chemoprevention with dietary phytochemicals, the heightened interest and challenges in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.
Full Text Available Abstract Dynamic chromatin structure is a fundamental property of gene transcriptional regulation, and has emerged as a critical modulator of physiological processes during cellular differentiation and development. Analysis of chromatin structure using molecular biology and biochemical assays in rare somatic stem and progenitor cells is key for understanding these processes but poses a great challenge because of their reliance on millions of cells. Through the development of a miniaturized genome-scale chromatin immunoprecipitation method (miniChIP–chip, we have documented the genome-wide chromatin states of low abundant populations that comprise hematopoietic stem cells and immediate progeny residing in murine bone marrow. In this report, we describe the miniChIP methodology that can be used for increasing an understanding of the epigenetic mechanisms underlying hematopoietic stem and progenitor cell function. Application of this method will reveal the contribution of dynamic chromatin structure in regulating the function of other somatic stem cell populations, and how this process becomes perturbed in pathological conditions. Additional file 1 Click here for file
Lin, Qiong; Wagner, Wolfgang
Aging is associated with highly reproducible DNA methylation (DNAm) changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA). Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a non-stochastic manner, particularly at CpGs that become hypermethylated upon aging in non-malignant tissues. This coordinated regulation in epigenetic aging signatures can therefore be used for aberrant epigenetic age-predictions, which facilitate disease stratification. For example, in acute myeloid leukemia (AML) higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age-predictions. Furthermore, epigenetic aging signatures correlate with overall survival in several types of cancer (such as lower grade glioma, glioblastoma multiforme, esophageal carcinoma, chromophobe renal cell carcinoma, cutaneous melanoma, lung squamous cell carcinoma, and neuroendocrine neoplasms). In conclusion, age-associated DNAm patterns in cancer are not related to chronological age of the patient, but they are coordinately regulated, particularly at CpGs that become hypermethylated in normal aging. Furthermore, the apparent epigenetic age-predictions correlate with clinical parameters and overall survival in several types of cancer, indicating that regulation of DNAm patterns in age-associated CpGs is relevant for cancer development.
Full Text Available Aging is associated with highly reproducible DNA methylation (DNAm changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA. Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a non-stochastic manner, particularly at CpGs that become hypermethylated upon aging in non-malignant tissues. This coordinated regulation in epigenetic aging signatures can therefore be used for aberrant epigenetic age-predictions, which facilitate disease stratification. For example, in acute myeloid leukemia (AML higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age-predictions. Furthermore, epigenetic aging signatures correlate with overall survival in several types of cancer (such as lower grade glioma, glioblastoma multiforme, esophageal carcinoma, chromophobe renal cell carcinoma, cutaneous melanoma, lung squamous cell carcinoma, and neuroendocrine neoplasms. In conclusion, age-associated DNAm patterns in cancer are not related to chronological age of the patient, but they are coordinately regulated, particularly at CpGs that become hypermethylated in normal aging. Furthermore, the apparent epigenetic age-predictions correlate with clinical parameters and overall survival in several types of cancer, indicating that regulation of DNAm patterns in age-associated CpGs is relevant for cancer development.
Synaptic plasticity is one of the most fundamental properties of neurons that underlie the formation of the memory in brain. In recent years, epigenetic modification of both DNA and histones such as DNA methylation and histone acetylation and methylation emerges as a potential regulatory mechanism that governs the transcription of several genes responsible for memory formation and behavior. Furthermore, the recent identification of nitrosylation of proteins has shown to either activate or repress gene transcription by modulating histone methylation or acetylation status in mature neuron. Recent studies suggest that the use of major substrates of abuse, e.g., cocaine, induces alterations in molecular and cellular mechanisms of epigenetics that underlie long-term memories in the striatum and prefrontal cortex. Moreover, downregulation of genes due to alterations in epigenetics leads to cognitive deficiencies associated with neurological disorders such as Alzheimer's disease, Huntington's disease, psychiatric disorder such as Rett's syndrome and aging. In this review, I will discuss the evidence for several epigenetic mechanisms in the coordination of complex memory formation and storage. In addition, I will address the current literature highlighting the role of acetylation and methylation of chromatin in memory impairment associated with several neurological disorders, aging, and addiction.
Ikegaki, Naohiko; Shimada, Hiroyuki; Fox, Autumn M; Regan, Paul L; Jacobs, Joshua R; Hicks, Sakeenah L; Rappaport, Eric F; Tang, Xao X
Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell-like NB cells that are phenotypically stable for more than a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSCs (iCSCs). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected s.c. into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSCs metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated large-cell NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, whereas the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest both that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells.
Full Text Available Epigenetic mechanisms such as DNA methylation and histone modification are important in stem cell differentiation. Methylation is principally associated with transcriptional repression, and histone acetylation is correlated with an active chromatin state. We determined the effects of these epigenetic mechanisms on adipocyte differentiation in mesenchymal stem cells (MSCs derived from bone marrow (BM-MSCs and adipose tissue (ADSCs using the chromatin-modifying agents trichostatin A (TSA, a histone deacetylase inhibitor, and 5-aza-2′-deoxycytidine (5azadC, a demethylating agent. Subconfluent MSC cultures were treated with 5, 50, or 500 nM TSA or with 1, 10, or 100 µM 5azadC for 2 days before the initiation of adipogenesis. The differentiation was quantified and expression of the adipocyte genes PPARG and FABP4 and of the anti-adipocyte gene GATA2 was evaluated. TSA decreased adipogenesis, except in BM-MSCs treated with 5 nM TSA. Only treatment with 500 nM TSA decreased cell proliferation. 5azadC treatment decreased proliferation and adipocyte differentiation in all conditions evaluated, resulting in the downregulation of PPARG and FABP4 and the upregulation of GATA2. The response to treatment was stronger in ADSCs than in BM-MSCs, suggesting that epigenetic memories may differ between cells of different origins. As epigenetic signatures affect differentiation, it should be possible to direct the use of MSCs in cell therapies to improve process efficiency by considering the various sources available.
Lee, Y W; Klein, C B; Kargacin, B; Salnikow, K; Kitahara, J; Dowjat, K; Zhitkovich, A; Christie, N T; Costa, M
A transgenic gpt+ Chinese hamster cell line (G12) was found to be susceptible to carcinogenic nickel-induced inactivation of gpt expression without mutagenesis or deletion of the transgene. Many nickel-induced 6-thioguanine-resistant variants spontaneously reverted to actively express gpt, as indicated by both reversion assays and direct enzyme measurements. Since reversion was enhanced in many of the nickel-induced variant cell lines following 24-h treatment with the demethylating agent 5-azacytidine, the involvement of DNA methylation in silencing gpt expression was suspected. This was confirmed by demonstrations of increased DNA methylation, as well as by evidence indicating condensed chromatin and heterochromatinization of the gpt integration site in 6-thioguanine-resistant cells. Upon reversion to active gpt expression, DNA methylation and condensation are lost. We propose that DNA condensation and methylation result in heterochromatinization of the gpt sequence with subsequent inheritance of the now silenced gene. This mechanism is supported by direct evidence showing that acute nickel treatment of cultured cells, and of isolated nuclei in vitro, can indeed facilitate gpt sequence-specific chromatin condensation. Epigenetic mechanisms have been implicated in the actions of some nonmutagenic carcinogens, and DNA methylation changes are now known to be important in carcinogenesis. This paper further supports the emerging theory that nickel is a human carcinogen that can alter gene expression by enhanced DNA methylation and compaction, rather than by mutagenic mechanisms.
Kristensen, Dina Graae; Mlynarska, Olga; Nielsen, John E
Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a s...
Sharma, Santosh Kumar; Yamamoto, Maki; Mukai, Yasuhiko
Epigenetic regulatory posttranslational histone modification marks not only function individually but also capable to act in combination as a unique pattern. A total of 16 plant species belonging to 11 genera of eight families (five dicots and three monocots) including land plants, epiphytes (orchids) and the holokinetic taxa (Drosera spp.) were analysed for chromosomal distribution of dual modified antiphospho (Ser10)-acetyl (K14)-histone H3 (H3S10phK14ac) to understand the combinatorial chromatin dynamics during mitotic cell division in plants. The anti-H3S10phK14ac evidently mark the pericentromeric chromatin on mitotic chromosomes of the plants excluding the holokinetic Drosera species, which revealed the immunolabelling of whole chromosomes all along the arms. The dual modified immunosignals were absent during early stages of mitosis, appeared intensively at metaphase and remained visible until late-anaphase/telophase however, labelled the whole chromosomes during meiotic metaphase I. Colocalization of anti-H3S10phK14ac with an onion's CENH3 antibody on mitotic chromosomes of Allium revealed the chromosomal location of anti-H3S10phK14ac in the region between signals for CENH3 detection. Overall analysis suggests that the unique localization of combinatorial histone modification mark at pericentromeric chromatin might have attributed through 'phospho-acetyl' cross talk that ultimately facilitate the sister chromatid cohesion at pericentromeres following condensation events in mitotic chromosomes. Here, we propose that dual modified H3S10phK14ac 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.
Signolet, Jason; Hendrich, Brian
Proteins that modify the structure of chromatin are known to be important for various aspects of metazoan biology including development, disease and possibly ageing. Yet functional details of why these proteins are important, i.e. how their action influences a given biological process, are lacking. While it is now possible to describe the biochemistry of how these proteins remodel chromatin, their chromatin binding profiles in cell lines, or gene expression changes upon loss of a given protein, in very few cases has this easily translated into an understanding of how the function of that protein actually influences a developmental process. Given that many chromatin modifying proteins will largely exert their influence through control of gene expression, it is useful to consider developmental processes as changes in the gene regulatory network (GRN), with each cell type exhibiting a unique gene expression profile. In this essay we consider the impact of two abundant and highly conserved chromatin modifying complexes, namely the nucleosome remodelling and deacetylation (NuRD) complex and the polycomb repressive complex 2 (PRC2), on the change in GRNs associated with lineage commitment during early mammalian development. We propose that while the NuRD complex limits the stability of cell states and defines the developmental trajectory between two stable states, PRC2 activity is important for stabilizing a new GRN once established. Although these two complexes display different biochemical activities, chromatin binding profiles and mutant phenotypes, we propose a model to explain how they cooperate to facilitate the transition through cell states that is development. © 2014 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS.
Ehrensberger, Andreas Hasso; Svejstrup, Jesper Qualmann
attributed to high kinetic barriers that affect all cells equally and can only be overcome by rare stochastic events. The barriers to reprogramming are likely to involve transformations of chromatin state because (i) inhibitors of chromatin-modifying enzymes can enhance the efficiency of reprogramming...... and (ii) knockdown or knock-out of chromatin-modifying enzymes can lower the efficiency of reprogramming. Here, we review the relationship between chromatin state transformations (chromatin reprogramming) and cellular reprogramming, with an emphasis on transcription factors, chromatin remodeling factors...
Simon, Jeffrey A; Lange, Carol A
The purpose of this research is to investigate the role of a chromatin-modifying enzyme called EZH2 in breast cancer epigenetics and to develop strategies to identify chemical inhibitors of this, enzyme...
Nakano, Megumi; Cardinale, Stefano; Noskov, Vladimir N.; Gassmann, Reto; Vagnarelli, Paola; Kandels-Lewis, Stefanie; Larionov, Vladimir; Earnshaw, William C.; Masumoto, Hiroshi
Summary We have used a human artificial chromosome (HAC) to manipulate the epigenetic state of chromatin within an active kinetochore. The HAC has a dimeric α-satellite repeat containing one natural monomer with a CENP-B binding site, and one completely artificial synthetic monomer with the CENP-B box replaced by a tetracycline operator (tetO). This HAC exhibits normal kinetochore protein composition and mitotic stability. Targeting of several tet-repressor (tetR) fusions into the centromere had no effect on kinetochore function. However, altering the chromatin state to a more open configuration with the tTA transcriptional activator or to a more closed state with the tTS transcription silencer caused missegregation and loss of the HAC. tTS binding caused the loss of CENP-A, CENP-B, CENP-C, and H3K4me2 from the centromere accompanied by an accumulation of histone H3K9me3. Our results reveal that a dynamic balance between centromeric chromatin and heterochromatin is essential for vertebrate kinetochore activity. PMID:18410728
Pikaard, Craig S; Mittelsten Scheid, Ortrun
The study of epigenetics in plants has a long and rich history, from initial descriptions of non-Mendelian gene behaviors to seminal discoveries of chromatin-modifying proteins and RNAs that mediate gene silencing in most eukaryotes, including humans. Genetic screens in the model plant Arabidopsis have been particularly rewarding, identifying more than 130 epigenetic regulators thus far. The diversity of epigenetic pathways in plants is remarkable, presumably contributing to the phenotypic plasticity of plant postembryonic development and the ability to survive and reproduce in unpredictable environments. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.
Pikaard, Craig S.; Mittelsten Scheid, Ortrun
The study of epigenetics in plants has a long and rich history, from initial descriptions of non-Mendelian gene behaviors to seminal discoveries of chromatin-modifying proteins and RNAs that mediate gene silencing in most eukaryotes, including humans. Genetic screens in the model plant Arabidopsis have been particularly rewarding, identifying more than 130 epigenetic regulators thus far. The diversity of epigenetic pathways in plants is remarkable, presumably contributing to the phenotypic plasticity of plant postembryonic development and the ability to survive and reproduce in unpredictable environments. PMID:25452385
Full Text Available Post-translational modifications of core histones play an important role in regulating fundamental biological processes such as DNA repair, transcription and replication. In this paper, we describe a novel assay that allows sequential targeting of distinct histone modifying enzymes to immobilized nucleosomal templates using recombinant chimeric targeting molecules. The assay can be used to study the histone substrate specificity of chromatin modifying enzymes as well as whether and how certain enzymes affect each other's histone modifying activities. As such the assay can help to understand how a certain histone code is established and interpreted.
Full Text Available As a consequence of acute kidney injury (AKI, proximal tubular cells hyperrespond to endotoxin (lipopolysaccharide, LPS by exaggerated renal Tnf-α Production. This LPS hyperresponsiveness is transcriptionally mediated. The epigenetic pathways that control these responses are unknown.We applied multiplex chromatin immunoprecipitation platform (Matrix ChIP to explore epigenetic pathways that underlie endotoxin hyperresponsiveness in the setting of preceding unilateral renal ischemia/reperfusion (I/R in mouse AKI model. Endotoxin exposure after I/R resulted in enhanced transcription, manifested by hyperresponsive recruitment of RNA polymerase II (Pol II at the Tnf-α gene. At this locus, LPS but not I/R increased levels of Pol II C-terminal domain (CTD phosho-serine2 &5 and induced dephosphorylation of the transcription-repressive histone H4 phospho-serine-1. In contrast, I/R but not LPS increased the transcription-permissive histone phosphorylation (H3 phospho-serine-10, H3.3 phospho-serine-31 at the Tnf-α gene. In agreement with these observations, I/R but not LPS increased activity of cognate kinases (Erk1/2, Msk1/2 and Aurora A at the Tnf-α locus. Cross-talk of histone phosphorylation and acetylation synergize to active gene expression. I/R and LPS increased histone acetylation. (H3K9/14Ac, H4K5/8/12/16Ac, H2KA5Ac, H2BK4/7Ac. Levels of some histone acetyltransferases at this gene (PCAF and MOF were increased by I/R but not by LPS, while others were induced by either I/R or LPS and exhibited endotoxin hyperresponsive patterns (GCN5, CBP and p300. The adaptor protein 14-3-3 couples histone phosphorylation with acetylation, and tethers chromatin modifiers/transcription elongation factors to target genes. Both I/R and LPS increased levels of 14-3-3 and several chromatin/transcription modifiers (BRD4, BRG1, HP-1γ and IKKα at the Tnf-α gene, all exhibiting endotoxin hyperresponsive recruitment patterns similar to Pol II.Our results suggest that
Latcheva, Nina K; Viveiros, Jennifer M; Waddell, Edward A; Nguyen, Phuong T T; Liebl, Faith L W; Marenda, Daniel R
We are beginning to appreciate the complex mechanisms by which epigenetic proteins control chromatin dynamics to tightly regulate normal development. However, the interaction between these proteins, particularly in the context of neuronal function, remains poorly understood. Here, we demonstrate that the activity of histone deacetylases (HDACs) opposes that of a chromatin remodeling enzyme at the Drosophila neuromuscular junction (NMJ). Pharmacological inhibition of HDAC function reverses loss of function phenotypes associated with Kismet, a chromodomain helicase DNA-binding (CHD) protein. Inhibition of HDACs suppresses motor deficits, overgrowth of the NMJ, and defective neurotransmission associated with loss of Kismet. We hypothesize that Kismet and HDACs may converge on a similar set of target genes in the nervous system. Our results provide further understanding into the complex interactions between epigenetic protein function in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.
Full Text Available Cell plasticity or potency is necessary for the formation of multiple cell types. The mechanisms underlying this plasticity are largely unknown. Preimplantation mouse embryos undergo drastic changes in cellular potency, starting with the totipotent zygote through to the formation of the pluripotent inner cell mass (ICM and differentiated trophectoderm in the blastocyst. Here, we set out to identify and functionally characterize chromatin modifiers that define the transitions of potency and cell fate in the mouse embryo. Using a quantitative microfluidics approach in single cells, we show that developmental transitions are marked by distinctive combinatorial profiles of epigenetic modifiers. Pluripotent cells of the ICM are distinct from their differentiated trophectoderm counterparts. We show that PRDM14 is heterogeneously expressed in 4-cell-stage embryos. Forced expression of PRDM14 at the 2-cell stage leads to increased H3R26me2 and can induce a pluripotent ICM fate. Our results shed light on the epigenetic networks that govern cellular potency and identity in vivo.
Wang, Fangnian; Deeney, Jude T.; Denis, Gerald V.
Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes, and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from Type 2 diabetes, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible target to treat obesity and diabetes through modulation of the function of a chromatin code reader. PMID:23374712
Mair, Barbara; Kubicek, Stefan; Nijman, Sebastian M B
Epigenetic deregulation is a hallmark of cancer, and there has been increasing interest in therapeutics that target chromatin-modifying enzymes and other epigenetic regulators. The rationale for applying epigenetic drugs to treat cancer is twofold. First, epigenetic changes are reversible, and drugs could therefore be used to restore the normal (healthy) epigenetic landscape. However, it is unclear whether drugs can faithfully restore the precancerous epigenetic state. Second, chromatin regulators are often mutated in cancer, making them attractive drug targets. However, in most instances it is unknown whether cancer cells are addicted to these mutated chromatin proteins, or whether their mutation merely results in epigenetic instability conducive to the selection of secondary aberrations. An alternative incentive for targeting chromatin regulators is the exploitation of cancer-specific vulnerabilities, including synthetic lethality, caused by epigenetic deregulation. We review evidence for the hypothesis that mechanisms other than oncogene addiction are a basis for the application of epigenetic drugs, and propose future research directions. Copyright © 2014 Elsevier Ltd. All rights reserved.
Full Text Available Downregulation of microRNAs (miRNAs at the 14q32 locus stabilizes the expression of cMYC, thus significantly contributing to osteosarcoma (OS pathobiology. Here, we show that downregulation of 14q32 miRNAs is epigenetically regulated. The predicted promoter regions of miRNA clusters at 14q32 locus showed no recurrent patterns of differential methylation, but Saos2 cells showed elevated histone deacetylase (HDAC activity. Treatment with 4-phenylbutyrate increased acetylation of histones associated with 14q32 miRNAs, but interestingly, robust restoration of 14q32 miRNA expression, attenuation of cMYC expression, and induction of apoptosis required concomitant treatment with 5-Azacytidine, an inhibitor of DNA methylation. These events were associated with genome-wide gene expression changes including induction of pro-apoptotic genes and downregulation of cell cycle genes. Comparable effects were achieved in human and canine OS cells using the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat and the DNA methylation inhibitor Zebularine (Zeb, with significantly more pronounced cytotoxicity in cells whose molecular phenotypes were indicative of aggressive biological behavior. These results suggested that the combination of these chromatin-modifying drugs may be a useful adjuvant in the treatment of rapidly progressive OS.
Satpathy, Shankha; Nabbi, Arash; Riabowol, Karl
The five human ING genes encode at least 15 splicing isoforms, most of which affect cell growth, differentiation and apoptosis through their ability to alter gene expression by epigenetic mechanisms. Since their discovery in 1996, ING proteins have been classified as type II tumour suppressors on the basis of reports describing their down-regulation and mislocalization in a variety of cancer types. In addition to their regulation by transcriptional mechanisms, understanding the range of PTMs (post-translational modifications) of INGs is important in understanding how ING functions are fine-tuned in the physiological setting and how they add to the repertoire of activities affected by the INGs. In the present paper we review the different PTMs that have been reported to occur on INGs. We discuss the PTMs that modulate ING function under normal conditions and in response to a variety of stresses. We also describe the ING PTMs that have been identified by several unbiased MS-based PTM enrichment techniques and subsequent proteomic analysis. Among the ING PTMs identified to date, a subset has been characterized for their biological significance and have been shown to affect processes including subcellular localization, interaction with enzymatic complexes and ING protein half-life. The present review aims to highlight the emerging role of PTMs in regulating ING function and to suggest additional pathways and functions where PTMs may effect ING function.
Full Text Available Genomic imprints-parental allele-specific DNA methylation marks at the differentially methylated regions (DMRs of imprinted genes-are erased and reestablished in germ cells according to the individual's sex. Imprint establishment at paternally methylated germ line DMRs occurs in fetal male germ cells. In prospermatogonia, the two unmethylated alleles exhibit different rates of de novo methylation at the H19/Igf2 imprinting control region (ICR depending on parental origin. We investigated the nature of this epigenetic memory using bisulfite sequencing and allele-specific ChIP-SNuPE assays. We found that the chromatin composition in fetal germ cells was biased at the ICR between the two alleles with the maternally inherited allele exhibiting more H3K4me3 and less H3K9me3 than the paternally inherited allele. We determined genetically that the chromatin bias, and also the delayed methylation establishment in the maternal allele, depended on functional CTCF insulator binding sites in the ICR. Our data suggest that, in primordial germ cells, maternally inherited allele-specific CTCF binding sets up allele-specific chromatin differences at the ICR. The erasure of these allele-specific chromatin marks is not complete before the process of de novo methylation imprint establishment begins. CTCF-dependent allele-specific chromatin composition imposes a maternal allele-specific delay on de novo methylation imprint establishment at the H19/Igf2 ICR in prospermatogonia.
Han, Pei; Li, Wei; Yang, Jin; Shang, Ching; Lin, Chiou-Hong; Cheng, Wei; Hang, Calvin T; Cheng, Hsiu-Ling; Chen, Chen-Hao; Wong, Johnson; Xiong, Yiqin; Zhao, Mingming; Drakos, Stavros G; Ghetti, Andrea; Li, Dean Y; Bernstein, Daniel; Chen, Huei-Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin
Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin-marked by H3K9 and CpG methylation-on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1-G9a/GLP-DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1-G9a-Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. Copyright © 2016. Published by Elsevier B.V.
George, Anuja A; Walworth, Nancy C
Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis. Genetic analysis implicates a histone deacetylase (HDAC)-linked pathway in suppression because HDAC mutants clr6-1, clr3∆, and sir2∆, though not hos2∆, also promote normal mitosis in the dis1-288 mutant. Suppression of the dis phenotype through loss of msc1 function requires the spindle checkpoint protein Mad2 and is limited by the presence of the heterochromatin-associated HP1 protein homolog Swi6. We speculate that alterations in histone acetylation promote a centromeric chromatin environment that compensates for compromised dis1 function by allowing for successful kinetochore-microtubule interactions that can satisfy the SAC. In cells arrested in mitosis by mutation of dis1, loss of function of epigenetic determinants such as Msc1 or specific HDACs can promote cell survival. Because the KDM5 family of proteins has been implicated in human cancers, an appreciation of the potential role of this family of proteins in chromosome segregation is warranted. Copyright © 2015 by the Genetics Society of America.
van Driel, R.
Chromatin molecules have properties that set them aside from all other biomacromolecules in the cell. (i) Chromosomes, which are single chromatin molecules, are the largest macromolecules in eukaryotic cells. (ii) Chromatin molecules carry the cell's genetic and epigenetic information and all
Tom C. Karagiannis
Full Text Available Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.
T.A. Knoch (Tobias); M. Wachsmuth (Malte); F.N. Kepper (Nick); M. Lesnussa (Michael); A. Abuseiris (Anis); Ali Imam, A.M.; P. Kolovos (Petros); G. Zuin; C. Kockx (Christel); R.W.W. Brouwer (Rutger); H.J.G. van de Werken (Harmen); W.F.J. van IJcken (Wilfred); K.S. Wendt (Kerstin); F.G. Grosveld (Frank)
textabstractBackground: The dynamic three-dimensional chromatin architecture of genomes and its co-evolutionary connection to its function - the storage, expression, and replication of genetic information - is still one of the central issues in biology. Here, we describe the much debated 3D
Zika, Eleni; Ting, Jenny P-Y
Recent advances have shown the crucial role of histone-modifying enzymes in controlling gene activation and repression. This led to the 'histone code' hypothesis, which proposes that combinations of histone modifications work in concert to affect specific gene expression. Mounting evidence suggests that the class II transactivator modulates promoter accessibility by coordinating the recruitment of chromatin modifiers in a time-dependent fashion. MHC-II expression is exquisitely controlled by these highly specific, coordinated and dynamic interactions at the promoter.
Full Text Available The isolation of stably transfected cell lines suitable for the manufacture of biotherapeutic protein products can be an arduous process relying on the identification of a high expressing clone; this frequently involves transgene amplification and maintenance of the clones' expression over at least 60 generations. Maintenance of expression, or cell line stability, is highly dependent upon the nature of the genomic environment at the site of transgene integration, where epigenetic mechanisms lead to variable expression and silencing in the vast majority of cases. We have assessed four chromatin function modifying elements (A2UCOE, MAR X_S29, STAR40 and cHS4 for their ability to negate chromatin insertion site position effects and their ability to express and maintain monoclonal antibody expression. Each element was analysed by insertion into different positions within a vector, either flanking or between heavy chain (HC and light chain (LC antibody expression cassettes. Our results clearly show that the A2UCOE is the most beneficial element in this system, with stable cell pools and clones increasing antibody yields 6.5-fold and 6.75-fold respectively. Stability analysis demonstrated that the reduction in antibody expression, seen with cells transfected with the control vector over 120 generations, was mitigated in the clones containing A2UCOE-augmented transgenes. Analysis also showed that the A2UCOE reduced the amount of transgene promoter DNA methylation, which contributed to the maintenance of starting levels of expression.
Wang, Fangnian; Deeney, Jude T; Denis, Gerald V
Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity-induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from insulin resistance, glucose intolerance and pancreatic beta cell dysfunction, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible, innovative target to treat obesity and diabetes through modulation of the function of a chromatin code reader. Copyright © 2013 Elsevier Inc. All rights reserved.
Amir T. Fathi
Full Text Available In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs, myeloproliferative neoplasms (MPNs, and acute myeloid leukemia (AML. Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors.
Jaworski, Diane M; Namboodiri, Aryan M A; Moffett, John R
Metabolic networks are significantly altered in neoplastic cells. This altered metabolic program leads to increased glycolysis and lipogenesis and decreased dependence on oxidative phosphorylation and oxygen consumption. Despite their limited mitochondrial respiration, cancer cells, nonetheless, derive sufficient energy from alternative carbon sources and metabolic pathways to maintain cell proliferation. They do so, in part, by utilizing fatty acids, amino acids, ketone bodies, and acetate, in addition to glucose. The alternative pathways used in the metabolism of these carbon sources provide opportunities for therapeutic manipulation. Acetate, in particular, has garnered increased attention in the context of cancer as both an epigenetic regulator of posttranslational protein modification, and as a carbon source for cancer cell biomass accumulation. However, to date, the data have not provided a clear understanding of the precise roles that protein acetylation and acetate oxidation play in carcinogenesis, cancer progression or treatment. This review highlights some of the major issues, discrepancies, and opportunities associated with the manipulation of acetate metabolism and acetylation-based signaling in cancer development and treatment. © 2015 Wiley Periodicals, Inc.
Forn, Marta; Muñoz, Mar; Tauriello, Daniele V F; Merlos-Suárez, Anna; Rodilla, Verónica; Bigas, Anna; Batlle, Eduard; Jordà, Mireia; Peinado, Miguel A
DNA methylation and chromatin remodeling are frequently implicated in the silencing of genes involved in carcinogenesis. Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types. However, it is unknown whether there is a coordinated regulation of the genes embedded in these regions in normal cells and in early stages of tumor progression. To better characterize the molecular events associated with the regulation and remodeling of these regions we analyzed two regions undergoing LRES in human colon cancer in the mouse model. We demonstrate that LRES also occurs in murine cancer in vivo and mimics the molecular features of the human phenomenon, namely, downregulation of gene expression, acquisition of inactive histone marks, and DNA hypermethylation of specific CpG islands. The genes embedded in these regions showed a dynamic and autonomous regulation during mouse intestinal cell differentiation, indicating that, in the framework considered here, the coordinated regulation in LRES is restricted to cancer. Unexpectedly, benign adenomas in Apc(Min/+) mice showed overexpression of most of the genes affected by LRES in cancer, which suggests that the repressive remodeling of the region is a late event. Chromatin immunoprecipitation analysis of the transcriptional insulator CTCF in mouse colon cancer cells revealed disrupted chromatin domain boundaries as compared with normal cells. Malignant regression of cancer cells by in vitro differentiation resulted in partial reversion of LRES and gain of CTCF binding. We conclude that genes in LRES regions are plastically regulated in cell differentiation and hyperproliferation, but are constrained to a coordinated repression by abolishing boundaries and the autonomous regulation of chromatin domains in cancer cells. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All
Bowersox, Karisa; Chopra, Surinder
Pericarp color 1 is a model system for the study of epigenetic gene regulation. It has more than 100 alleles that contribute to the color of the pericarp and cob glume of maize. Unstable factor for orange 1 (Ufo1) is a spontaneous dominant mutation that leads to a gain in pigmentation due to a decrease in methylation in p1 genes. This decrease in methylation of cytosine in the DNA leads to changes in chromatin structure. Finding the mechanism for this spontaneous mutation can lead to way of preventing the mutation increasing production colorless maize for food production. Through genotyping and phenotyping fine gene mapping, gene expression and whole genome profiling can be accomplished for plants with the Ufo1 mutation present.
Pawlyn, Charlotte; Kaiser, Martin F; Heuck, Christoph; Melchor, Lorenzo; Wardell, Christopher P; Murison, Alex; Chavan, Shweta S; Johnson, David C; Begum, Dil B; Dahir, Nasrin M; Proszek, Paula Z; Cairns, David A; Boyle, Eileen M; Jones, John R; Cook, Gordon; Drayson, Mark T; Owen, Roger G; Gregory, Walter M; Jackson, Graham H; Barlogie, Bart; Davies, Faith E; Walker, Brian A; Morgan, Gareth J
Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR. ©2016 American Association for Cancer Research.
Mirabella, Anne C; Foster, Benjamin M; Bartke, Till
The regulation of chromatin by epigenetic mechanisms plays a central role in gene expression and is essential for development and maintenance of cell identity and function. Aberrant chromatin regulation is observed in many diseases where it leads to defects in epigenetic gene regulation resulting in pathological gene expression programmes. These defects are caused by inherited or acquired mutations in genes encoding enzymes that deposit or remove DNA and histone modifications and that shape chromatin architecture. Chromatin deregulation often results in neurodevelopmental disorders and intellectual disabilities, frequently linked to physical and developmental abnormalities, but can also cause neurodegenerative diseases, immunodeficiency, or muscle wasting syndromes. Epigenetic diseases can either be of monogenic origin or manifest themselves as complex multifactorial diseases such as in congenital heart disease, autism spectrum disorders, or cancer in which mutations in chromatin regulators are contributing factors. The environment directly influences the epigenome and can induce changes that cause or predispose to diseases through risk factors such as stress, malnutrition or exposure to harmful chemicals. The plasticity of chromatin regulation makes targeting the enzymatic machinery an attractive strategy for therapeutic intervention and an increasing number of small molecule inhibitors against a variety of epigenetic regulators are in clinical use or under development. In this review, we will give an overview of the molecular lesions that underlie epigenetic diseases, and we will discuss the impact of the environment and prospects for epigenetic therapies.
Full Text Available In living cells, DNA is packaged along with protein and RNA into chromatin. Chemical modifications to nucleotides and histone proteins are added, removed and recognized by multi-functional molecular complexes. Here I define a new computational model, in which chromatin modifications are information units that can be written onto a one-dimensional string of nucleosomes, analogous to the symbols written onto cells of a Turing machine tape, and chromatin-modifying complexes are modeled as read-write rules that operate on a finite set of adjacent nucleosomes. I illustrate the use of this "chromatin computer" to solve an instance of the Hamiltonian path problem. I prove that chromatin computers are computationally universal--and therefore more powerful than the logic circuits often used to model transcription factor control of gene expression. Features of biological chromatin provide a rich instruction set for efficient computation of nontrivial algorithms in biological time scales. Modeling chromatin as a computer shifts how we think about chromatin function, suggests new approaches to medical intervention, and lays the groundwork for the engineering of a new class of biological computing machines.
In living cells, DNA is packaged along with protein and RNA into chromatin. Chemical modifications to nucleotides and histone proteins are added, removed and recognized by multi-functional molecular complexes. Here I define a new computational model, in which chromatin modifications are information units that can be written onto a one-dimensional string of nucleosomes, analogous to the symbols written onto cells of a Turing machine tape, and chromatin-modifying complexes are modeled as read-write rules that operate on a finite set of adjacent nucleosomes. I illustrate the use of this “chromatin computer” to solve an instance of the Hamiltonian path problem. I prove that chromatin computers are computationally universal – and therefore more powerful than the logic circuits often used to model transcription factor control of gene expression. Features of biological chromatin provide a rich instruction set for efficient computation of nontrivial algorithms in biological time scales. Modeling chromatin as a computer shifts how we think about chromatin function, suggests new approaches to medical intervention, and lays the groundwork for the engineering of a new class of biological computing machines. PMID:22567109
Liu, Kai; Ding, Lianggong; Li, Yuhong; Yang, Hui; Zhao, Chunyue; Lei, Ye; Han, Shuting; Tao, Wei; Miao, Dengshun; Steller, Hermann; Welsh, Michael J.; Liu, Lei
Neuronal necrosis induced by calcium overload causes devastating brain dysfunction in diseases such as stroke and brain trauma. It has been considered a stochastic event lacking genetic regulation, and pharmacological means to suppress neuronal necrosis are lacking. Using a Drosophila model of calcium overloading, we found JIL-1/mitogen- and stress-activated protein kinase 1/2 is a regulator of neuronal necrosis through phosphorylation of histone H3 serine 28 (H3S28ph). Further, we identified its downstream events including displacement of polycomb repressive complex 1 (PRC1) and activation of Trithorax (Trx). To test the role of JIL-1/PRC1/Trx cascade in mammals, we studied the necrosis induced by glutamate in rat cortical neuron cultures and rodent models of brain ischemia and found the cascade is activated in these conditions and inhibition of the cascade suppresses necrosis in vitro and in vivo. Together, our research demonstrates that neuronal necrosis is regulated by a chromatin-modifying cascade, and this discovery may provide potential therapeutic targets and biomarkers for neuronal necrosis. PMID:25201987
Eukaryotic cells contain several hundred ribosomal RNA (rRNA) genes (rDNA), a fraction of them being silenced by epigenetic mechanisms. The presence of two epigenetically distinct states of rRNA genes provides a unique opportunity to decipher the molecular mechanisms that establish the euchromatic, i.e. transcriptionally active, and the heterochromatic, i.e. transcriptionally silent, state of rDNA. This article summarizes our knowledge of the epigenetic mechanisms that control rDNA transcription and emphasizes how DNA methyltransferases and histone-modifying enzymes work in concert with chromatin-remodeling complexes and RNA-guided mechanisms to establish a specific chromatin structure that defines the transcriptional state of rRNA genes. These studies exemplify the mutual dependence and complex crosstalk among different epigenetic players in the alteration of the chromatin structure during the process of gene activation or silencing.
Full Text Available Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGFR, targeting Brd4 and targeting Jumonji histone demethylases.
Das, Laxmidhar; Parbin, Sabnam; Pradhan, Nibedita; Kausar, Chahat; Patra, Samir K
Infertility is a complex pathophysiological condition. It may caused by specific or multiple physical and physiological factors, including abnormalities in homeostasis, hormonal imbalances and genetic alterations. In recent times various studies implicated that, aberrant epigenetic mechanisms are associated with reproductive infertility. There might be transgenerational effects associated with epigenetic modifications of gametes and studies suggest the importance of alterations in epigenetic modification at early and late stages of gametogenesis. To determine the causes of infertility it is necessary to understand the altered epigenetic modifications of associated gene and mechanisms involved therein. This review is devoted to elucidate the recent mechanistic advances in regulation of genes by epigenetic modification and emphasizes their possible role related to reproductive infertility. It includes environmental, nutritional, hormonal and physiological factors and influence of internal structural architecture of chromatin nucleosomes affecting DNA and histone modifications in both male and female gametes, early embryogenesis and offspring. Finally, we would like to emphasize that research on human infertility by gene knock out of epigenetic modifiers genes must be relied upon animal models.
James C Robertson
Full Text Available Lysine specific demethylase-1 (LSD1/KDM1A in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date. Recently, extended molecular dynamics (MD simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners.
Saze, Hidetoshi; Kakutani, Tetsuji
Epigenetically silent transposons and repeats constitute a substantial proportion of eukaryotic genomes, but their impact on cellular gene function remains largely unexplored. In Arabidopsis, transposons are silenced by DNA methylation, and this methylation is often abolished by mutations in a chromatin-remodeling gene DDM1 (DECREASE IN DNA METHYLATION 1). The ddm1 mutation induces various types of developmental abnormalities through de-repression of transposons and repeats. Here, we report a novel mechanism for a ddm1-induced syndrome, called bonsai (bns). We identified the gene responsible for the bns phenotypes by genetic linkage analysis and subsequent transcriptional analysis. The bns phenotypes are due to silencing of a putative Anaphase-Promoting Complex (APC) 13 gene. The BNS gene silencing was associated with DNA hypermethylation, which is in contrast to the ddm1-induced hypomethylation in the other genomic regions. This paradoxical BNS hypermethylation was reproducibly induced during self-pollination of the ddm1 mutant, and it was mediated by a long interspersed nuclear element (LINE) retrotransposon flanking the BNS gene. We discuss possible molecular mechanisms and the evolutionary implications of transposon-mediated epigenetic changes in the BNS locus.
Hammond, Colin; Strømme, Caroline Bianchi; Huang, Hongda
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....
Hosokawa, Mika; Tanaka, Shota; Ueda, Kumiko; Iwakawa, Seigo
Limited information is currently available on how to apply epigenetic modifiers to current colorectal cancer (CRC) chemotherapy. The purpose of this study is to clarify the schedule-dependent effects of combined treatment with conventional anticancer drugs and epigenetic modifiers in human CRC cells. Cytotoxicity in 4 CRC cell lines (SW480, HT29, SW48, and HCT116) was measured using the WST-8 assay. As epigenetic modifiers, 3 DNA methyltransferase (DNMT) inhibitors such as decitabine (DAC), azacytidine (AC), and zebularine (Zeb), and 3 histone deacetylase (HDAC) inhibitors including trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and valproic acid (VPA) were used. Combination effects were analyzed by the isobologram method. SW480 cells showed the lowest sensitivity to the anticancer drugs 5-fluorouracil, SN-38 (the active form of irinotecan), and oxaliplatin. In SW480 cells, epigenetic modifiers other than VPA showed the most significant synergistic effects when used before anticancer drugs, while VPA showed synergistic effects in co- or post-treatment. In the 3 other CRC cells, synergistic effects were less frequent and weaker. The dose of anticancer drugs may be reduced by combining epigenetic modifiers in SW480 cells, which are less sensitive to anticancer drugs, unlike the more sensitive HT29, SW48, and HCT116 cell lines. These results provide useful information for understanding how to incorporate epigenetic modifiers into current CRC chemotherapy.
Romani, Massimo; Pistillo, Maria Pia; Banelli, Barbara
Epigenetics provides the key to transform the genetic information into phenotype and because of its reversibility it is considered an ideal target for therapeutic interventions. This paper reviews the basic mechanisms of epigenetic control: DNA methylation, histone modifications, chromatin remodeling, and ncRNA expression and their role in disease development. We describe also the influence of the environment, lifestyle, nutritional habits, and the psychological influence on epigenetic marks and how these factors are related to cancer and other diseases development. Finally we discuss the potential use of natural epigenetic modifiers in the chemoprevention of cancer to link together public health, environment, and lifestyle. PMID:26339624
Romani, Massimo; Pistillo, Maria Pia; Banelli, Barbara
Epigenetics provides the key to transform the genetic information into phenotype and because of its reversibility it is considered an ideal target for therapeutic interventions. This paper reviews the basic mechanisms of epigenetic control: DNA methylation, histone modifications, chromatin remodeling, and ncRNA expression and their role in disease development. We describe also the influence of the environment, lifestyle, nutritional habits, and the psychological influence on epigenetic marks and how these factors are related to cancer and other diseases development. Finally we discuss the potential use of natural epigenetic modifiers in the chemoprevention of cancer to link together public health, environment, and lifestyle.
Kramer, Jamie M
Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders.
Maleszewska, Marta; Kaminska, Bozena, E-mail: B.Kaminska@nencki.gov.pl [Laboratory of Molecular Neurobiology, Neurobiology Center, The Nencki Institute of Experimental Biology, 3 Pasteur Str., Warsaw 02-093 (Poland)
Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target DNA and have been implicated in both normal cell differentiation and oncogenic transformation. Epigenetic abnormalities can occur both as a cause and as a consequence of cancer. Oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of DNA methylation or histone modifications. In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development. Epigenetic-based mechanisms are reversible and the possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. Gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. We discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens.
Zingg, Daniel; Debbache, Julien; Schaefer, Simon M; Tuncer, Eylul; Frommel, Sandra C; Cheng, Phil; Arenas-Ramirez, Natalia; Haeusel, Jessica; Zhang, Yudong; Bonalli, Mario; McCabe, Michael T; Creasy, Caretha L; Levesque, Mitchell P; Boyman, Onur; Santoro, Raffaella; Shakhova, Olga; Dummer, Reinhard; Sommer, Lukas
Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.
Full Text Available The dynamic and differential regulation and expression of genes is majorly governed by the complex interactions of a subset of biomolecules in the cell operating at multiple levels starting from genome organisation to protein post-translational regulation. The regulatory layer contributed by the epigenetic layer has been one of the favourite areas of interest recently. This layer of regulation as we know today largely comprises of DNA modifications, histone modifications and noncoding RNA regulation and the interplay between each of these major components. Epigenetic regulation has been recently shown to be central to development of a number of disease processes. The availability of datasets of high-throughput screens for molecules for biological properties offer a new opportunity to develop computational methodologies which would enable in-silico screening of large molecular libraries.In the present study, we have used data from high throughput screens for the inhibitors of epigenetic modifiers. Computational predictive models were constructed based on the molecular descriptors. Machine learning algorithms for supervised training, Naive Bayes and Random Forest, were used to generate predictive models for the small molecule inhibitors of histone methyl-transferases and demethylases. Random forest, with the accuracy of 80%, was identified as the most accurate classifier. Further we complemented the study with substructure search approach filtering out the probable pharmacophores from the active molecules leading to drug molecules.We show that effective use of appropriate computational algorithms could be used to learn molecular and structural correlates of biological activities of small molecules. The computational models developed could be potentially used to screen and identify potential new biological activities of molecules from large molecular libraries and prioritise them for in-depth biological assays. To the best of our knowledge, this is
Mehta, Aditi; Dobersch, Stephanie; Romero-Olmedo, Addi J; Barreto, Guillermo
Lung cancer is the leading cause of cancer-related deaths worldwide. The initiation and progression of lung cancer is the result of the interaction between permanent genetic and dynamic epigenetic alterations. DNA methylation is the best studied epigenetic mark in human cancers. Altered DNA methylation in cancer was identified in 1983. Within 30 years of this discovery, DNA methylation inhibitors are used clinically to treat a variety of cancers, highlighting the importance of the epigenetic basis of cancer. In addition, histone modifications, nucleosome remodeling, and micro RNA (miRNA)-mediated gene regulation are also fundamental to tumor genesis. Distinct chromatin alterations occur in all stages of lung cancer, including initiation, growth, and metastasis. Therefore, stage-specific epigenetic changes can be used as powerful and reliable tools for early diagnosis of lung cancer and to monitor patient prognosis. Moreover, since epigenetic changes are dynamic and reversible, chromatin modifiers are promising targets for the development of more effective therapeutic strategies against cancer. This review summarizes the chromatin alterations in lung cancer, focusing on the diagnostic and therapeutic approaches targeting epigenetic modifications that could help to reduce the high case-fatality rate of this dreadful disease.
Ferreyra-Solari, Nazarena; Belforte, Fiorella S.; Canedo, Lucía; Videla-Richardson, Guillermo A.; Espinosa, Joaquín M.; Rossi, Mario; Serna, Eva; Riudavets, Miguel A.; Martinetto, Horacio; Sevlever, Gustavo; Perez-Castro, Carolina
KANSL2 is an integral subunit of the Non-Specific Lethal (NSL) chromatin-modifying complex which contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. PMID:27406830
Makatsori, Dimitra; Kourmouli, Niki; Polioudaki, Hara; Shultz, Leonard D; McLean, Kelvin; Theodoropoulos, Panayiotis A; Singh, Prim B; Georgatos, Spyros D
Using heterochromatin-enriched fractions, we have detected specific binding of mononucleosomes to the N-terminal domain of the inner nuclear membrane protein lamin B receptor. Mass spectrometric analysis reveals that LBR-associated particles contain complex patterns of methylated/acetylated histones and are devoid of "euchromatic" epigenetic marks. LBR binds heterochromatin as a higher oligomer and forms distinct nuclear envelope microdomains in vivo. The organization of these membrane assemblies is affected significantly in heterozygous ic (ichthyosis) mutants, resulting in a variety of structural abnormalities and nuclear defects.
Glass, Jacob L; Hassane, Duane; Wouters, Bas J; Kunimoto, Hiroyoshi; Avellino, Roberto; Garrett-Bakelman, Francine E; Guryanova, Olga A; Bowman, Robert; Redlich, Shira; Intlekofer, Andrew M; Meydan, Cem; Qin, Tingting; Fall, Mame; Alonso, Alicia; Guzman, Monica L; Valk, Peter J M; Thompson, Craig B; Levine, Ross; Elemento, Olivier; Delwel, Ruud; Melnick, Ari; Figueroa, Maria E
We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, whereas those with dominant hypomethylation displayed greater disruption of distal and intronic regions. Mutations in IDH and DNMT3A had opposing and mutually exclusive effects on the epigenome. Notably, co-occurrence of both mutations resulted in epigenetic antagonism, with most CpGs affected by either mutation alone no longer affected in double-mutant AMLs. Importantly, this epigenetic antagonism precedes malignant transformation and can be observed in preleukemic LSK cells from Idh2(R140Q) or Dnmt3a(R882H) single-mutant and Idh2(R140Q)/Dnmt3a(R882H) double-mutant mice. Notably, IDH/DNMT3A double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition ex vivo as compared with AMLs with either single mutation.Significance: AML is biologically heterogeneous with subtypes characterized by specific genetic and epigenetic abnormalities. Comprehensive DNA methylation profiling revealed that differential methylation of nonpromoter regulatory elements is a driver of epigenetic identity, that gene mutations can be context-dependent, and that co-occurrence of mutations in epigenetic modifiers can result in epigenetic antagonism. Cancer Discov; 7(8); 868-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783. ©2017 American Association for Cancer Research.
Epigenetic silencing of human immunodeficiency virus (HIV) transcription by formation of restrictive chromatin structures at the viral long terminal repeat drives the progressive entry of HIV into latency.
Pearson, Richard; Kim, Young Kyeung; Hokello, Joseph; Lassen, Kara; Friedman, Julia; Tyagi, Mudit; Karn, Jonathan
The molecular mechanisms utilized by human immunodeficiency virus (HIV) to enter latency are poorly understood. Following the infection of Jurkat T cells with lentiviral vectors that express Tat in cis, gene expression is progressively silenced. Silencing is greatly enhanced when the lentiviral vectors carry an attenuated Tat gene with the H13L mutation. Individual clones of lentivirus-infected cells showed a wide range of shutdown rates, with the majority showing a 50% silencing frequency between 30 to 80 days. The silenced clones characteristically contained a small fraction (0 to 15%) of activated cells that continued to express d2EGFP. When d2EGFP(+) and d2EGFP(-) cell populations were isolated from the shutdown clones, they quickly reverted to the original distribution of inactive and active cells, suggesting that the d2EGFP(+) cells arise from stochastic fluctuations in gene expression. The detailed analysis of transcription initiation and elongation using chromatin immunoprecipitation (ChIP) assays confirms that Tat levels are restricted in the latently infected cells but gradually rise during proviral reactivation. ChIP assays using clones of latently infected cells demonstrate that the latent proviruses carry high levels of deacetylated histones and trimethylated histones. In contrast, the cellular genes IkappaB alpha and GAPDH had high levels of acetylated histones and no trimethylated histones. The levels of trimethylated histone H3 and HP1-alpha associated with HIV proviruses fell rapidly after tumor necrosis factor alpha activation. The progressive shutdown of HIV transcription following infection suggests that epigenetic mechanisms targeting chromatin structures selectively restrict HIV transcription initiation. This decreases Tat production below the levels that are required to sustain HIV gene expression.
Siersbæk, Rasmus; Nielsen, Ronni; Mandrup, Susanne
remodeling have revealed 'snapshots' of this cascade and the chromatin landscape at specific time-points of differentiation. These studies demonstrate that multiple adipogenic transcription factors co-occupy hotspots characterized by an open chromatin structure and specific epigenetic modifications...
Epigenetic variation, such as changes in DNA methylations, regulatory small RNAs (sRNAs) and chromatin modifications can be induced by environmental stress. There is increasing information that such induced epigenetic modifications can be transmitted to offspring, potentially mediating adaptive
Strunnikova Maria; Schagdarsurengin, Undraga; Kehlen, Astrid; Garbe, James C.; Stampfer, Martha R.; Dammann, Reinhard
Epigenetic inactivation of the RASSF1A tumor suppressor by CpG island methylation was frequently detected in cancer. However, the mechanisms of this aberrant DNA methylation are unknown. In the RASSF1A promoter, we characterized four Sp1 sites, which are frequently methylated in cancer. We examined the functional relationship between DNA methylation, histone modification, Sp1 binding, and RASSF1A expression in proliferating human mammary epithelial cells. With increasing passages, the transcription of RASSF1A was dramatically silenced. This inactivation was associated with deacetylation and lysine 9 trimethylation of histone H3 and an impaired binding of Sp1 at the RASSF1A promoter. In mammary epithelial cells that had overcome a stress-associated senescence barrier, a spreading of DNA methylation in the CpG island promoter was observed. When the RASSF1A-silenced cells were treated with inhibitors of DNA methyltransferase and histone deacetylase, binding of Sp1 and expression of RASSF1 A reoccurred. In summary, we observed that histone H3 deacetylation and H3 lysine 9 trimethylation occur in the same time window as gene inactivation and precede DNA methylation. Our data suggest that in epithelial cells, histone inactivation may trigger de novo DNA methylation of the RASSF1A promoter and this system may serve as a model for CpG island inactivation of tumor suppressor genes.
Lim, Pek Siew; Li, Jasmine; Holloway, Adele F; Rao, Sudha
T cells are exquisitely poised to respond rapidly to pathogens and have proved an instructive model for exploring the regulation of inducible genes. Individual genes respond to antigenic stimulation in different ways, and it has become clear that the interplay between transcription factors and the chromatin platform of individual genes governs these responses. Our understanding of the complexity of the chromatin platform and the epigenetic mechanisms that contribute to transcriptional control has expanded dramatically in recent years. These mechanisms include the presence/absence of histone modification marks, which form an epigenetic signature to mark active or inactive genes. These signatures are dynamically added or removed by epigenetic enzymes, comprising an array of histone-modifying enzymes, including the more recently recognized chromatin-associated signalling kinases. In addition, chromatin-remodelling complexes physically alter the chromatin structure to regulate chromatin accessibility to transcriptional regulatory factors. The advent of genome-wide technologies has enabled characterization of the chromatin landscape of T cells in terms of histone occupancy, histone modification patterns and transcription factor association with specific genomic regulatory regions, generating a picture of the T-cell epigenome. Here, we discuss the multi-layered regulation of inducible gene expression in the immune system, focusing on the interplay between transcription factors, and the T-cell epigenome, including the role played by chromatin remodellers and epigenetic enzymes. We will also use IL2, a key inducible cytokine gene in T cells, as an example of how the different layers of epigenetic mechanisms regulate immune responsive genes during T-cell activation. © 2013 John Wiley & Sons Ltd.
Kheir, Tony Bou; Lund, Anders H.
Progression of the mammalian cell cycle depends on correct timing and co-ordination of a series of events, which are managed by the cellular transcriptional machinery and epigenetic mechanisms governing genome accessibility. Epigenetic chromatin modifications are dynamic across the cell cycle...... a correct inheritance of epigenetic chromatin modifications to daughter cells. In this chapter, we summarize the current knowledge on the dynamics of epigenetic chromatin modifications during progression of the cell cycle....
Full Text Available In the context of regenerative medicine, based on the potential of stem cells to restore diseased tissues, epigenetics is becoming a pivotal area of interest. Therapeutic interventions that promote tissue and organ regeneration have as primary objective the selective control of gene expression in adult stem cells. This requires a deep understanding of the epigenetic mechanisms controlling transcriptional programs in tissue progenitors. This review attempts to elucidate the principle epigenetic regulations responsible of stem cells differentiation. In particular we focus on the current understanding of the epigenetic networks that regulate differentiation of muscle progenitors by the concerted action of chromatin-modifying enzymes and noncoding RNAs. The novel exciting role of exosome-bound microRNA in mediating epigenetic information transfer is also discussed. Finally we show an overview of the epigenetic strategies and therapies that aim to potentiate muscle regeneration and counteract the progression of Duchenne Muscular Dystrophy (DMD.
Berdasco, María; Esteller, Manel
The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein-Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders.
Belzil, Veronique V; Katzman, Rebecca B; Petrucelli, Leonard
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50 % of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate, or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanucleotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. Epigenetic processes regulate DNA replication and repair, RNA transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. Transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control DNA methylation, histone modifications, and RNA editing. While the alteration of DNA methylation and histone modification has recently been reported in ALS and FTD, the assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. As the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating ALS and FTD, especially for sporadic cases. Here, we provide a review of what is currently known about altered epigenetic processes in both ALS and FTD and discuss potential therapeutic strategies targeting epigenetic mechanisms. As approximately 85 % of ALS and FTD cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the
Smith, Owen K; Aladjem, Mirit I
The DNA replication program is, in part, determined by the epigenetic landscape that governs local chromosome architecture and directs chromosome duplication. Replication must coordinate with other biochemical processes occurring concomitantly on chromatin, such as transcription and remodeling, to insure accurate duplication of both genetic and epigenetic features and to preserve genomic stability. The importance of genome architecture and chromatin looping in coordinating cellular processes on chromatin is illustrated by two recent sets of discoveries. First, chromatin-associated proteins that are not part of the core replication machinery were shown to affect the timing of DNA replication. These chromatin-associated proteins could be working in concert, or perhaps in competition, with the transcriptional machinery and with chromatin modifiers to determine the spatial and temporal organization of replication initiation events. Second, epigenetic interactions are mediated by DNA sequences that determine chromosomal replication. In this review, we summarize recent findings and current models linking spatial and temporal regulation of the replication program with epigenetic signaling. We discuss these issues in the context of the genome's three-dimensional structure with an emphasis on events occurring during the initiation of DNA replication. Published by Elsevier Ltd.
Kanwal, Rajnee; Gupta, Karishma; Gupta, Sanjay
Epigenetic and genetic alterations contribute to cancer initiation and progression. Epigenetics refers to the study of heritable changes in gene expression without alterations in DNA sequences. Epigenetic changes are reversible and include key processes of DNA methylation, chromatin modifications, nucleosome positioning, and alterations in noncoding RNA profiles. Disruptions in epigenetic processes can lead to altered gene function and cellular neoplastic transformation. Epigenetic modifications precede genetic changes and usually occur at an early stage in neoplastic development. Recent technological advances offer a better understanding of the underlying epigenetic alterations during carcinogenesis and provide insight into the discovery of putative epigenetic biomarkers for detection, prognosis, risk assessment, and disease monitoring. In this chapter we provide information on various epigenetic mechanisms and their role in carcinogenesis, in particular, epigenetic modifications causing genetic changes and the potential clinical impact of epigenetic research in the future.
The characteristics of epigenetic control, including the potential for long-lasting, stable effects on gene expression that outlive an initial transient signal, could be of singular importance for post-mitotic neurons, which are subject to changes with short- to long-lasting influence on their activity and connectivity. Persistent changes in chromatin structure are thought to contribute to mechanisms of epigenetic inheritance. Recent advances in chromatin biology offer new avenues to investig...
The SWI/SNF (SWItch/Sucrose NonFermentable or BAF, Brg/Brahma-associated factors) complexes are epigenetic modifiers of chromatin structure and undergo progressive changes in subunit composition during cellular differentiation. For example, in embryonic stem cells (ESCs) esBAF contains Brg1 and Baf...
Fass, D M; Schroeder, F A; Perlis, R H; Haggarty, S J
Developing novel therapeutics and diagnostic tools based upon an understanding of neuroplasticity is critical in order to improve the treatment and ultimately the prevention of a broad range of nervous system disorders. In the case of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), where diagnoses are based solely on nosology rather than pathophysiology, there exists a clear unmet medical need to advance our understanding of the underlying molecular mechanisms and to develop fundamentally new mechanism experimental medicines with improved efficacy. In this context, recent preclinical molecular, cellular, and behavioral findings have begun to reveal the importance of epigenetic mechanisms that alter chromatin structure and dynamically regulate patterns of gene expression that may play a critical role in the pathophysiology of mood disorders. Here, we will review recent advances involving the use of animal models in combination with genetic and pharmacological probes to dissect the underlying molecular mechanisms and neurobiological consequence of targeting this chromatin-mediated neuroplasticity. We discuss evidence for the direct and indirect effects of mood stabilizers, antidepressants, and antipsychotics, among their many other effects, on chromatin-modifying enzymes and on the epigenetic state of defined genomic loci, in defined cell types and in specific regions of the brain. These data, as well as findings from patient-derived tissue, have also begun to reveal alterations of epigenetic mechanisms in the pathophysiology and treatment of mood disorders. We summarize growing evidence supporting the notion that selectively targeting chromatin-modifying complexes, including those containing histone deacetylases (HDACs), provides a means to reversibly alter the acetylation state of neuronal chromatin and beneficially impact neuronal activity-regulated gene transcription and mood-related behaviors. Looking beyond current knowledge
Carmell, Michelle A; Hannon, Gregory J
.... However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulating cellular gene expression...
.... However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulation cellular gene expression...
Carmell, Michelle A; Hannon, Gregory J
.... However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulating cellular gene expression...
Full Text Available Epigenetic changes, such as DNA methylation or histone modification, can remodel the chromatin and regulate gene expression. Remodeling of chromatin provides an efficient mechanism of transducing signals, such as light or nutrient availability, to regulate gene expression. CLOCK:BMAL1 mediated activation of clock-controlled genes (CCGs is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Recent research has demonstrated that chromatin remodeling is at the cross-roads of circadian rhythms and regulation of metabolism and aging. It would be of interest to identify if similar pathways exist in the epigenetic regulation of memory formation.
Zaidi, Sayyed K; Trombly, Daniel J; Dowdy, Christopher R; Lian, Jane B; Stein, Janet L; van Wijnen, Andre J; Stein, Gary S
Focal organization of regulatory machinery within the interphase nucleus is linked to biological responsiveness and perturbed in cancer. Lineage determinant Runx proteins organize and assemble multi-protein complexes at sites of transcription within the nucleus and regulate both RNA polymerase II- and I-mediated gene expression. In addition, Runx proteins epigenetically control lineage determining transcriptional programs including: 1) architectural organization of macromolecular complexes in interphase, 2) regulation of gene expression through bookmarking during mitosis, and 3) microRNA-mediated translational control in the interphase nucleus. These mechanisms are compromised with the onset and progression of cancer. For example, the oncogenic AML1-ETO protein, which results from a chromosomal translocation between chromosomes 8 and 21, is expressed in nearly 25% of all acute myelogenous leukemias, disrupts Runx1 subnuclear localization during interphase and compromises transcriptional regulation. Epigenetically, the leukemic protein redirects the Runx1 DNA binding domain to leukemia-specific nuclear microenvironments, modifies regulatory protein accessibility to Runx1 target genes by imprinting repressive chromatin marks, and deregulates the microRNA (miR) profile of diseased myeloid cells. Consequently, the entire Runx1-dependent transcriptional program of myeloid cells is deregulated leading to onset and progression of acute myeloid leukemia and maintenance of leukemic phenotype. We discuss the potential of modified epigenetic landscape of leukemic cells as a viable therapeutic target. Copyright © 2012. Published by Elsevier Ltd.
Fransz, P.F.; Jong, de J.H.
Recent studies in yeast, animals and plants have provided major breakthroughs in unraveling the molecular mechanism of higher-order gene regulation. In conjunction with the DNA code, proteins that are involved in chromatin remodeling, histone modification and epigenetic imprinting form a large
Seffer, Istvan; Nemeth, Zoltan; Hoffmann, Gyula; Matics, Robert; Seffer, A Gergely; Koller, Akos
Morphological and functional changes of cells are important for adapting to environmental changes and associated with continuous regulation of gene expressions. Genes are regulated-in part-by epigenetic mechanisms resulting in alternating patterns of gene expressions throughout life. Epigenetic changes responding to the environmental and intercellular signals can turn on/off specific genes, but do not modify the DNA sequence. Most epigenetic mechanisms are evolutionary conserved in eukaryotic organisms, and several homologs of epigenetic factors are present in plants and animals. Moreover, in vitro studies suggest that the plant cytoplasm is able to induce a nuclear reassembly of the animal cell, whereas others suggest that the ooplasm is able to induce condensation of plant chromatin. Here, we provide an overview of the main epigenetic mechanisms regulating gene expression and discuss fundamental epigenetic mechanisms and factors functioning in both plants and animals. Finally, we hypothesize that animal genome can be reprogrammed by epigenetic factors from the plant protoplast.
De Gobbi Marco
Full Text Available Abstract Background In self-renewing, pluripotent cells, bivalent chromatin modification is thought to silence (H3K27me3 lineage control genes while 'poising' (H3K4me3 them for subsequent activation during differentiation, implying an important role for epigenetic modification in directing cell fate decisions. However, rather than representing an equivalently balanced epigenetic mark, the patterns and levels of histone modifications at bivalent genes can vary widely and the criteria for identifying this chromatin signature are poorly defined. Results Here, we initially show how chromatin status alters during lineage commitment and differentiation at a single well characterised bivalent locus. In addition we have determined how chromatin modifications at this locus change with gene expression in both ensemble and single cell analyses. We also show, on a global scale, how mRNA expression may be reflected in the ratio of H3K4me3/H3K27me3. Conclusions While truly 'poised' bivalently modified genes may exist, the original hypothesis that all bivalent genes are epigenetically premarked for subsequent expression might be oversimplistic. In fact, from the data presented in the present work, it is equally possible that many genes that appear to be bivalent in pluripotent and multipotent cells may simply be stochastically expressed at low levels in the process of multilineage priming. Although both situations could be considered to be forms of 'poising', the underlying mechanisms and the associated implications are clearly different.
Landry, Christopher D; Kandel, Eric R; Rajasethupathy, Priyamvada
In recent years, a greater understanding has emerged of the role epigenetic mechanisms play in the brain, not only during development, but also in mature neurons involved in long-term memory. The identification of spatially and temporally tuned epigenetic modification of genetic loci during memory storage has revealed the remarkably input-responsive, target-specific, and long-term nature of epigenetic regulation, but the underlying mechanisms have remained elusive. New insight into these mechanisms has come from the study of small RNAs, which have emerged as regulators that can confer sequence specificity to DNA- and chromatin-modifying processes. We discuss advances in the elucidation of the epigenetic mechanisms involved in long-term memory, focusing on the role of small RNAs, and in particular piwi-interacting RNAs (piRNAs), in the epigenetic regulation underlying memory storage. Copyright © 2013 Elsevier Ltd. All rights reserved.
van Otterdijk, Sanne D; Michels, Karin B
Epigenetics plays an important role in orchestrating key biologic processes. Epigenetic marks, including DNA methylation, histones, chromatin structure, and noncoding RNAs, are modified throughout life in response to environmental and behavioral influences. With each new generation, DNA methylation patterns are erased in gametes and reset after fertilization, probably to prevent these epigenetic marks from being transferred from parents to their offspring. However, some recent animal studies suggest an apparent resistance to complete erasure of epigenetic marks during early development, enabling transgenerational epigenetic inheritance. Whether there are similar mechanisms in humans remains unclear, with the exception of epigenetic imprinting. Nevertheless, a distinctly different mechanism-namely, intrauterine exposure to environmental stressors that may affect establishment of the newly composing epigenetic patterns after fertilization-is often confused with transgenerational epigenetic inheritance. In this review, we delineate the definition of and requirement for transgenerational epigenetic inheritance, differentiate it from the consequences of intrauterine exposure, and discuss the available evidence in both animal models and humans.-Van Otterdijk, S. D., Michels, K. B. Transgenerational epigenetic inheritance in mammals: how good is the evidence? © FASEB.
Hewitt, Kyle J; Sanalkumar, Rajendran; Johnson, Kirby D; Keles, Sunduz; Bresnick, Emery H
Erythropoiesis, in which hematopoietic stem cells (HSCs) generate lineage-committed progenitors that mature into erythrocytes, is regulated by numerous chromatin modifying and remodeling proteins. We will focus on how epigenetic and genetic mechanisms mesh to establish the erythroid transcriptome and how studying erythropoiesis can yield genomic principles. Trans-acting factor binding to small DNA motifs (cis-elements) underlies regulatory complex assembly at specific chromatin sites, and therefore unique transcriptomes. As cis-elements are often very small, thousands or millions of copies of a given element reside in a genome. Chromatin restricts factor access in a context-dependent manner, and cis-element-binding factors recruit chromatin regulators that mediate functional outputs. Technologies to map chromatin attributes of loci in vivo, to edit genomes and to sequence whole genomes have been transformative in discovering critical cis-elements linked to human disease. Cis-elements mediate chromatin-targeting specificity, and chromatin regulators dictate cis-element accessibility/function, illustrating an amalgamation of genetic and epigenetic mechanisms. Cis-elements often function ectopically when studied outside of their endogenous loci, and complex strategies to identify nonredundant cis-elements require further development. Facile genome-editing technologies provide a new approach to address this problem. Extending genetic analyses beyond exons and promoters will yield a rich pipeline of cis-element alterations with importance for red cell biology and disease.
Romagnolo, Donato F; Daniels, Kevin D; Grunwald, Jonathan T; Ramos, Stephan A; Propper, Catherine R; Selmin, Ornella I
Reduced expression of tumor suppressor genes (TSG) increases the susceptibility to breast cancer. However, only a small percentage of breast tumors is related to family history and mutational inactivation of TSG. Epigenetics refers to non-mutational events that alter gene expression. Endocrine disruptors found in foods and drinking water may disrupt epigenetically hormonal regulation and increase breast cancer risk. This review centers on the working hypothesis that agonists of the aromatic hydrocarbon receptor (AHR), bisphenol A (BPA), and arsenic compounds, induce in TSG epigenetic signatures that mirror those often seen in sporadic breast tumors. Conversely, it is hypothesized that bioactive food components that target epigenetic mechanisms protect against sporadic breast cancer induced by these disruptors. This review highlights (i) overlaps between epigenetic signatures placed in TSG by AHR-ligands, BPA, and arsenic with epigenetic alterations associated with sporadic breast tumorigenesis; and (ii) potential opportunities for the prevention of sporadic breast cancer with food components that target the epigenetic machinery. Characterizing the overlap between epigenetic signatures elicited in TSG by endocrine disruptors with those observed in sporadic breast tumors may afford new strategies for breast cancer prevention with specific bioactive food components or diet. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Lund, Anders H; van Lohuizen, Maarten
Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development....... This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic...
Kozub, Meghan M; Carr, Ryan M; Lomberk, Gwen L; Fernandez-Zapico, Martin E
Histone-modifying enzymes play a critical role in chromatin remodeling and are essential for influencing several genome processes such as gene expression and DNA repair, replication, and recombination. The discovery of lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, dramatically revolutionized research in the field of epigenetics. LSD1 plays a pivotal role in a wide range of biological operations, including development, cellular differentiation, embryonic pluripotency, and disease (for example, cancer). This mini-review focuses on the role of LSD1 in chromatin regulatory complexes, its involvement in epigenetic changes throughout development, and its importance in physiological and pathological processes.
Mariana P Torrente
Full Text Available Chromatin proteins provide a scaffold for DNA packaging and a basis for epigenetic regulation and genomic maintenance. Despite understanding its functional roles, mapping the chromatin proteome (i.e. the "Chromatome" is still a continuing process. Here, we assess the biological specificity and proteomic extent of three distinct chromatin preparations by identifying proteins in selected chromatin-enriched fractions using mass spectrometry-based proteomics. These experiments allowed us to produce a chromatin catalog, including several proteins ranging from highly abundant histone proteins to less abundant members of different chromatin machinery complexes. Using a Normalized Spectral Abundance Factor approach, we quantified relative abundances of the proteins across the chromatin enriched fractions giving a glimpse into their chromosomal abundance. The large-scale data sets also allowed for the discovery of a variety of novel post-translational modifications on the identified chromatin proteins. With these comparisons, we find one of the probed methods to be qualitatively superior in specificity for chromatin proteins, but inferior in proteomic extent, evidencing a compromise that must be made between biological specificity and broadness of characterization. Additionally, we attempt to identify proteins in eu- and heterochromatin, verifying the enrichments by characterizing the post-translational modifications detected on histone proteins from these chromatin regions. In summary, our results provide insights into the value of different methods to extract chromatin-associated proteins and provide starting points to study the factors that may be involved in directing gene expression and other chromatin-related processes.
Milavetz, Barry I; Balakrishnan, Lata
DNA tumor viruses including members of the polyomavirus, adenovirus, papillomavirus, and herpes virus families are presently the subject of intense interest with respect to the role that epigenetics plays in control of the virus life cycle and the transformation of a normal cell to a cancer cell. To date, these studies have primarily focused on the role of histone modification, nucleosome location, and DNA methylation in regulating the biological consequences of infection. Using a wide variety of strategies and techniques ranging from simple ChIP to ChIP-chip and ChIP-seq to identify histone modifications, nuclease digestion to genome wide next generation sequencing to identify nucleosome location, and bisulfite treatment to MeDIP to identify DNA methylation sites, the epigenetic regulation of these viruses is slowly becoming better understood. While the viruses may differ in significant ways from each other and cellular chromatin, the role of epigenetics appears to be relatively similar. Within the viral genome nucleosomes are organized for the expression of appropriate genes with relevant histone modifications particularly histone acetylation. DNA methylation occurs as part of the typical gene silencing during latent infection by herpesviruses. In the simple tumor viruses like the polyomaviruses, adenoviruses, and papillomaviruses, transformation of the cell occurs via integration of the virus genome such that the virus's normal regulation is disrupted. This results in the unregulated expression of critical viral genes capable of redirecting cellular gene expression. The redirected cellular expression is a consequence of either indirect epigenetic regulation where cellular signaling or transcriptional dysregulation occurs or direct epigenetic regulation where epigenetic cofactors such as histone deacetylases are targeted. In the more complex herpersviruses transformation is a consequence of the expression of the viral latency proteins and RNAs which again can
Groth, Anja; Rocha, Walter; Verreault, Alain
Inheritance and maintenance of the DNA sequence and its organization into chromatin are central for eukaryotic life. To orchestrate DNA-replication and -repair processes in the context of chromatin is a challenge, both in terms of accessibility and maintenance of chromatin organization. To meet...... the challenge of maintenance, cells have evolved efficient nucleosome-assembly pathways and chromatin-maturation mechanisms that reproduce chromatin organization in the wake of DNA replication and repair. The aim of this Review is to describe how these pathways operate and to highlight how the epigenetic...... landscape may be stably maintained even in the face of dramatic changes in chromatin structure....
Statham, A.L.; Robinson, M.D.; Song, J.Z.; Coolen, M.W.; Stirzaker, C.; Clark, S. J.
The complex relationship between DNA methylation, chromatin modification, and underlying DNA sequence is often difficult to unravel with existing technologies. Here, we describe a novel technique based on high-throughput sequencing of bisulfite-treated chromatin immunoprecipitated DNA (BisChIP-seq),
Milagro, F I; Mansego, M L; De Miguel, C; Martínez, J A
Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding the importance of the
Montero-Conde, Cristina; Leandro-Garcia, Luis J; Chen, Xu; Oler, Gisele; Ruiz-Llorente, Sergio; Ryder, Mabel; Landa, Iñigo; Sanchez-Vega, Francisco; La, Konnor; Ghossein, Ronald A; Bajorin, Dean F; Knauf, Jeffrey A; Riordan, Jesse D; Dupuy, Adam J; Fagin, James A
Oncogenic RAS mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with Hras(G12V) in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in Tpo-Cre/homozygous FR-Hras(G12V) mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SB-induced tumors identified 45 recurrently mutated candidate cancer genes. These mutation profiles were remarkably concordant with mutated cancer genes identified in a large series of human poorly differentiated and anaplastic thyroid cancers screened by next-generation sequencing using the MSK-IMPACT panel of cancer genes, which we modified to include all SB candidates. The disrupted genes primarily clustered in chromatin remodeling functional nodes and in the PI3K pathway. ATXN7, a component of a multiprotein complex with histone acetylase activity, scored as a significant SB hit. It was recurrently mutated in advanced human cancers and significantly co-occurred with RAS or NF1 mutations. Expression of ATXN7 mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to ATXN7 as a previously unrecognized cancer gene.
Jarillo, José A; Piñeiro, Manuel; Cubas, Pilar; Martínez-Zapater, José M
Plant development results from specific patterns of gene expression that are tightly regulated in a spatio-temporal manner. Chromatin remodeling plays a central role in establishing these expression patterns and maintaining epigenetic transcriptional states through successive rounds of mitosis that take place within a cell lineage. Plant epigenetic switches occur not only at the embryo stage, but also during postembryonic developmental transitions, suggesting that chromatin remodeling activities in plants can provide a higher degree of regulatory flexibility which probably underlies their developmental plasticity. Here, we highlight recent progress in the understanding of plant chromatin dynamic organization, facilitating the activation or repression of specific sets of genes involved in different developmental programs and integrating them with the response to environmental signals. Chromatin conformation controls gene expression both in actively dividing undifferentiated cells and in those already fate-determined. In this context, we first describe chromatin reorganization activities required to maintain meristem function stable through DNA replication and cell division. Organ initiation at the apex, with emphasis on reproductive development, is next discussed to uncover the chromatin events involved in the establishment and maintenance of expression patterns associated with differentiating cells; this is illustrated with the complex epigenetic regulation of the Arabidopsis floral repressor FLOWERING LOCUS C (FLC). Finally, we discuss the involvement of chromatin remodeling in plant responses to environmental cues and to different types of stress conditions.
Leturcq, Maïté; Lefebvre, Tony; Vercoutter-Edouart, Anne-Sophie
Post-translational modifications of histones and the dynamic DNA methylation cycle are finely regulated by a myriad of chromatin-binding factors and chromatin-modifying enzymes. Epigenetic modifications ensure local changes in the architecture of chromatin, thus controlling in fine the accessibility of the machinery of transcription, replication or DNA repair to the chromatin. Over the past decade, the nutrient-sensor enzyme O-GlcNAc transferase (OGT) has emerged as a modulator of chromatin remodeling. In mammals, OGT acts either directly through dynamic and reversible O-GlcNAcylation of histones and chromatin effectors, or in an indirect manner through its recruitment into chromatin-bound multiprotein complexes. In particular, there is an increasing amount of evidence of a cross-talk between OGT and the DNA dioxygenase ten-eleven translocation proteins that catalyze active DNA demethylation. Conversely, the stability of OGT itself can be controlled by the histone lysine-specific demethylase 2 (LSD2). Finally, a few studies have explored the role of O-GlcNAcase (OGA) in chromatin remodeling. In this review, we summarize the recent findings on the link between OGT, OGA and chromatin regulators in mammalian cellular models, and discuss their relevance in physiological and pathological conditions. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
Full Text Available The burgeoning field of epigenetics is beginning to make a significant impact on our understanding of tissue development, maintenance, and function. Epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues that direct cell-type specific gene networks. The inner ear is comprised of highly specialized cell types with identical genomes that originate from a single totipotent zygote. During inner ear development specific combinations of transcription factors and epigenetic modifiers must function in a coordinated manner to establish and maintain cellular identity. These epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns. In this review, we highlight emerging paradigms for epigenetic modifications related to inner ear development, and how epigenetics may have a significant role in hearing loss, protection, and regeneration.
Michieletto, Davide; Chiang, Michael; Colì, Davide; Papantonis, Argyris; Orlandini, Enzo; Cook, Peter R; Marenduzzo, Davide
Reconciling the stability of epigenetic patterns with the rapid turnover of histone modifications and their adaptability to external stimuli is an outstanding challenge. Here, we propose a new biophysical mechanism that can establish and maintain robust yet plastic epigenetic domains via genomic bookmarking (GBM). We model chromatin as a recolourable polymer whose segments bear non-permanent histone marks (or colours) which can be modified by 'writer' proteins. The three-dimensional chromatin organisation is mediated by protein bridges, or 'readers', such as Polycomb Repressive Complexes and Transcription Factors. The coupling between readers and writers drives spreading of biochemical marks and sustains the memory of local chromatin states across replication and mitosis. In contrast, GBM-targeted perturbations destabilise the epigenetic patterns. Strikingly, we demonstrate that GBM alone can explain the full distribution of Polycomb marks in a whole Drosophila chromosome. We finally suggest that our model provides a starting point for an understanding of the biophysics of cellular differentiation and reprogramming. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Catherine M Scahill
Full Text Available KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing. In addition to effects on translation and DNA replication gene expression, high-replicate RNA-seq in morphologically normal individuals demonstrates a stable regulatory response of epigenetic modifiers and the specific de-repression of a group of zinc finger genes residing in constitutive heterochromatin. Together our data reveal a complex role for Kdm2aa in regulating normal mRNA levels and carcinogenesis. These findings establish kdm2aa mutants as the first single gene knockout model of melanoma biology.
Helin, Kristian; Dhanak, Dashyant
is a frequent event in disease, and the first epigenetic-based therapies for cancer treatment have been approved. A generation of new classes of potent and specific inhibitors for several chromatin-associated proteins have shown promise in preclinical trials. Although the biology of epigenetic regulation......A plethora of groundbreaking studies have demonstrated the importance of chromatin-associated proteins and post-translational modifications of histones, proteins and DNA (so-called epigenetic modifications) for transcriptional control and normal development. Disruption of epigenetic control...
Full Text Available Acute myeloid leukemia (AML, a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently “hit” genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event. Increasing body of evidence demonstrates that chromatin modification aberrations underlying the formation of blood cancer can be reversed by pharmacological targeting of the responsible epigenetic modulators, thus providing new mechanism-based treatment strategies. Here, we summarize recent advances in development of small-molecule inhibitors specific to chromatin factors and their potential applications in the treatment of genetically defined AMLs. These compounds selectively inhibit various subclasses of “epigenetic writers” (such as histone methyltransferases MLL/KMT2A, G9A/KMT1C, EZH2/KMT6A, DOT1L/KMT4, and PRMT1, “epigenetic readers” (such as BRD4 and plant homeodomain finger proteins, and “epigenetic erasers” (such as histone demethylases LSD1/KDM1A and JMJD2C/KDM4C. We also discuss about the molecular mechanisms underpinning therapeutic effect of these epigenetic compounds in AML and favor their potential usage for combinational therapy and treatment of pre-leukemia diseases.
Wotton, David; Pemberton, Lucy F; Merrill-Schools, Jacqueline
Many of the known SUMO substrates are nuclear proteins, which regulate gene expression and chromatin dynamics. Sumoylation, in general, appears to correlate with decreased transcriptional activity, and in many cases modulation of the chromatin template is implicated. Sumoylation of the core histones is associated with transcriptional silencing, and transcription factor sumoylation can decrease gene expression by promoting recruitment of chromatin modifying enzymes. Additionally, sumoylation of transcriptional corepressors and chromatin remodeling enzymes can influence interactions with other transcriptional regulators, and alter their enzymatic activity. In some cases, proteins that are components of transcriptional corepressor complexes have been shown to be SUMO E3 ligases, further emphasizing the integration of sumoylation with the regulation of chromatin remodeling. Despite the evidence suggesting that sumoylation is primarily repressive for access to chromatin, recent analyses suggest that protein sumoylation on the chromatin template may play important roles at highly expressed genes. Elucidating the dynamic interplay of sumoylation with other post-translational modifications of histones and chromatin associated proteins will be key to fully understanding the regulation of access to the chromatin template.
Razvi, Enal S
The field of epigenetics is now on a geometric rise, driven in a large part by the realization that modifiers of chromatin are key regulators of biological processes in vivo. The three major classes of epigenetic effectors are DNA methylation, histone post-translational modifications (such as acetylation, methylation or phosphorylation) and small noncoding RNAs (most notably microRNAs). In this article, I report from Select Biosciences Epigenetics Europe 2010 industry conference held on 14-15 September 2010 at The Burlington Hotel, Dublin, Ireland. This industry conference was extremely well attended with a global pool of delegates representing the academic research community, biotechnology companies and pharmaceutical companies, as well as the technology/tool developers. This conference represented the current state of the epigenetics community with cancer/oncology as a key driver. In fact, it has been estimated that approximately 45% of epigenetic researchers today identify cancer/oncology as their main area of focus vis-à-vis their epigenetic research efforts.
Cabot, Birgit; Cabot, Ryan A
The mammalian embryo undergoes a dramatic amount of epigenetic remodeling during the first week of development. In this review, we discuss several epigenetic changes that happen over the course of cleavage development, focusing on covalent marks (e.g., histone methylation and acetylation) and non-covalent remodeling (chromatin remodeling via remodeling complexes; e.g., SWI/SNF-mediated chromatin remodeling). Comparisons are also drawn between remodeling events that occur in embryos from a variety of mammalian species. © 2018 Society for Reproduction and Fertility.
Tallen, Gesche; Riabowol, Karl
Cancer cells accumulate genetic and epigenetic changes that alter gene expression to drive tumorigenesis. Epigenetic silencing of tumor suppressor, cell cycle, differentiation and DNA repair genes contributes to neoplastic transformation. The ING (inhibitor of growth) proteins (ING1-ING5) have emerged as a versatile family of growth regulators, phospholipid effectors, histone mark sensors and core components of HDAC1/2 - and several HAT chromatin-modifying complexes. This review will describe the characteristic pathways by which ING family proteins differentially affect the Hallmarks of Cancer and highlight the various epigenetic mechanisms by which they regulate gene expression. Finally, we will discuss their potentials as biomarkers and therapeutic targets in epigenetic treatment strategies. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Hassler, Melanie R; Schiefer, Ana-Iris; Egger, Gerda
Non-Hodgkin's lymphomas (NHLs) comprise a large and diverse group of neoplasms of lymphocyte origin with heterogeneous molecular features and clinical manifestations. Current therapies are based on standard chemotherapy, immunotherapy, radiation or stem cell transplantation. The discovery of recurrent mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases, has provided researchers with a rationale to develop novel inhibitors targeting these enzymes. Several clinical and preclinical studies have demonstrated the efficacy of epigenetic drugs in NHL therapy and a few specific inhibitors have already been approved for clinical use. Here, we provide an overview of current NHL classification and a review of the present literature describing epigenetic alterations in NHL, including a summary of different epigenetic drugs, and their use in preclinical and clinical studies.
Shevchenko G. V.
Full Text Available Plants can apply various strategies to minimize environmental impact. One of the strategies is heritable modifications of gene expression which occur without changing original DNA sequence and are known as epigenetic. Signaling pathway Rb-E2F (retinoblastoma (Rb-transcription factor E2F/DP connects the cell cycle with factors, modifying structure of chromatin and DNA. It also coordinates cell proliferation and differentiation influenced by external stimuli. The article highlights the activity of Rb-E2F/DP signaling pathway and its connection with the epigenetic changes of DNA in plants.
Lokken, Alyson A.; Zeleznik-Le, Nancy J.
KDM1A/LSD1, a histone H3K4/K9 demethylase and epigenetic regulator with roles in both gene activation and repression, has increased expression in multiple cancer types. Harris et al., in this issue of Cancer Cell, and Schenk et al. show that KDM1A may be a viable therapeutic target in treating AML.
Martínez, J. Alfredo; Milagro, Fermín I.; Claycombe, Kate J.; Schalinske, Kevin L.
Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them. PMID:24425725
Maio, Michele; Covre, Alessia; Fratta, Elisabetta; Di Giacomo, Anna Maria; Taverna, Pietro; Natali, Pier Giorgio; Coral, Sandra; Sigalotti, Luca
Epigenetic regulation allows heritably modulating gene expression profiles without modifying the primary sequence of gDNA. Under physiologic conditions, epigenetic patterns determine tissue-specific gene expression landscapes, gene imprinting, inactivation of chromosome X, and preservation of genomic stability. The most characterized mediators of epigenetic inheritance are gDNA methylation and histone posttranslational modifications that cooperate to alter chromatin state and genome transcription. According to these notions, it is not surprising that cancer cells invariantly deploy epigenetic alterations to achieve gene expression patterns required for neoplastic transformation and tumor progression. In this context, the recently uncovered use of epigenetic alterations by cancer cells to become stealth from the host's immune recognition has significant immunobiologic relevance in tumor progression, and it appears to have potential clinical usefulness. Indeed, immune evasion is among the major obstacles to further improve the efficacy of cancer immunotherapies and to increase long-lasting disease control. Luckily, different "epigenetic drugs" able to revert these "epimutations" are available, some of which have already been approved for clinical use. Here, we summarize the immunomodulatory activities of epigenetic drugs that lead to improved immune recognition of cancer cells and focus on the potential of this class of agents in improving the anticancer activity of novel immunotherapies through combinatorial epigenetic immunotherapy approaches. ©2015 American Association for Cancer Research.
Eid, Aseel; Zawia, Nasser
Lead exposure has primarily been a concern during development in young children and little attention has been paid to exposure outcomes as these children age, or even to exposures in adulthood. Childhood exposures have long term consequences, and adults who have been exposed to lead as children show a host of cognitive deficits. Lead has also been shown to induce latent changes in the aging brain, and has been implicated in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's Disease, and Parkinson's. Recent research has shown that lead has the ability to alter DNA methylation, histone modifications, and miRNA expression in experimental models, and in humans. These findings implicate epigenetics in lead induced toxicity, and long term changes in individuals. Epigenetic modification could potentially provide us a mechanism by which the environment, and toxic exposures contribute to the increased susceptibility of adult neurodegenerative disease. Copyright © 2016 Elsevier B.V. All rights reserved.
Lokken, Alyson A; Zeleznik-Le, Nancy J
KDM1A/LSD1, a histone H3K4/K9 demethylase and epigenetic regulator with roles in both gene activation and repression, has increased expression in multiple cancer types. Harris et al., in this issue of Cancer Cell, and Schenk et al. show that KDM1A may be a viable therapeutic target in treating AML. Copyright © 2012 Elsevier Inc. All rights reserved.
Moonat, Sachin; Pandey, Subhash C.
Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker’s dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity—for example, by modifying the structure of the DNA–protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism. PMID:23584115
Heller, Elizabeth A; Cates, Hannah M; Peña, Catherine J; Sun, Haosheng; Shao, Ningyi; Feng, Jian; Golden, Sam A; Herman, James P; Walsh, Jessica J; Mazei-Robison, Michelle; Ferguson, Deveroux; Knight, Scott; Gerber, Mark A; Nievera, Christian; Han, Ming-Hu; Russo, Scott J; Tamminga, Carol S; Neve, Rachael L; Shen, Li; Zhang, H Steve; Zhang, Feng; Nestler, Eric J
Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.
Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: firstname.lastname@example.org [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)
Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.
Technological and methodological advances, in particular next-generation sequencing and chromatin profiling, has led to a deluge of data on epigenetic mechanisms and processes. Epigenetic regulation in the brain is no exception. In this commentary, Ehud Lamm writes that extending existing frameworks for thinking about psychological development to…
Whitelaw, Nadia C; Chong, Suyinn; Morgan, Daniel K; Nestor, Colm; Bruxner, Timothy J; Ashe, Alyson; Lambley, Eleanore; Meehan, Richard; Whitelaw, Emma
Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans. © 2010 Whitelaw et al.; licensee BioMed Central Ltd.
Sciacovelli, Marco; Gonçalves, Emanuel; Johnson, Timothy Isaac; Zecchini, Vincent Roberto; da Costa, Ana Sofia Henriques; Gaude, Edoardo; Drubbel, Alizee Vercauteren; Theobald, Sebastian Julian; Abbo, Sandra Riekje; Tran, Maxine Gia Binh; Rajeeve, Vinothini; Cardaci, Simone; Foster, Sarah; Yun, Haiyang; Cutillas, Pedro; Warren, Anne; Gnanapragasam, Vincent; Gottlieb, Eyal; Franze, Kristian; Huntly, Brian; Maher, Eamonn Richard; Maxwell, Patrick Henry; Saez-Rodriguez, Julio; Frezza, Christian
Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.
Menéndez, Pablo; Villarejo, Pedro; Padilla, David; Menéndez, José María; Rodríguez Montes, José Antonio
The epigenetic and physiological mechanisms that alter the structure of chromatin include the methylation of DNA, changes in the histones, and changes in RNA. A literature review has been carried out using PubMed on the evidence published on the association between epigenetics and colorectal cancer. The scientific literature shows that epigenetic changes, such as genetic modifications may be very significant in the origin of neoplastic disease, contributing both to the development and progression of the disease. Copyright © 2011 AEC. Published by Elsevier Espana. All rights reserved.
Cells often exhibit different and stable phenotypes from the same DNA sequence. Robustness and plasticity of such cellular states are controlled by diverse transcriptional and epigenetic mechanisms, among them the modification of biochemical marks on chromatin. Here, we develop a stochastic model that describes the dynamics of epigenetic marks along a given DNA region. Through mathematical analysis, we show the emergence of bistable and persistent epigenetic states from the cooperative recruitment of modifying enzymes. We also find that the dynamical system exhibits a critical point and displays, in the presence of asymmetries in recruitment, a bifurcation diagram with hysteresis. These results have deep implications for our understanding of epigenetic regulation. In particular, our study allows one to reconcile within the same formalism the robust maintenance of epigenetic identity observed in differentiated cells, the epigenetic plasticity of pluripotent cells during differentiation, and the effects of epigenetic misregulation in diseases. Moreover, it suggests a possible mechanism for developmental transitions where the system is shifted close to the critical point to benefit from high susceptibility to developmental cues.
Sookoian, Silvia; Gianotti, Tomas Fernández; Burgueño, Adriana L; Pirola, Carlos J
A growing body of evidence supports the notion that epigenetic changes such as DNA methylation and histone modifications, both involving chromatin remodeling, contribute to fetal metabolic programming...
Senyildiz, Mine; Karaman, Ecem Fatma; Bas, Serap Sancar; Pirincci, Pelin Arda; Ozden, Sibel
Bisphenol A (BPA), an estrogenic endocrine disruptor, is widely used in the production of polycarbonate plastic and epoxy resins, resulting in high risk on human health. In present study we aimed to investigate the effects of BPA on global and gene specific DNA methylation, global histone modifications and regulation of chromatin modifiying enzymes in human neuroblastoma cells (SH-SY5Y). Cells were treated with BPA at 0.1, 1 and 10μM concentrations for 48 and 96h. IC50 value of BPA was determined as 183 and 129μM in SH-SY5Y cells after 24h by MTT and NRU tests, respectively. We observed significant alterations on the 5-mC% levels (1.3 fold) and 5-hmC% levels (1.67 fold) after 10μM of BPA for 96h. Significant decrease was identified in H3K9me3 and H3K9ac after 10μM of BPA for 96h while decrease was observed in H3K4me3 at 10μM of BPA for 48h. Alterations were observed in chromatin modifiying genes including G9a, EZH2, SETD8, SETD1A, HAT1, SIRT1, DNMT1, RIZ1 and Suv39h1 after 96h of BPA exposure. Taken together, this study suggests that BPA might modulate the epigenetic regulators which would be key molecular events in the toxicity of endocrine disrupting chemicals. Copyright © 2017 Elsevier Ltd. All rights reserved.
Alexandra Teresa Pires Carvalho
Full Text Available We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM and hybrid quantum mechanics/molecular mechanics (QM/MM methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts.
Bhat, J; Helmuth, J; Chitadze, G; Kouakanou, L; Peters, C; Vingron, M; Ammerpohl, O; Kabelitz, D
Epigenetic marks including histone modifications and DNA methylation are associated with the regulation of gene expression and activity. In addition, an increasing number of non-coding RNAs with regulatory activity on gene expression have been identified. Alongside, technological advancements allow for the analysis of these mechanisms with high resolution up to the single-cell level. For instance, the assay for transposase-accessible chromatin using sequencing (ATAC-seq) simultaneously probes for chromatin accessibility and nucleosome positioning. Thus, it provides information on two levels of epigenetic regulation. Development and differentiation of T cells into functional subset cells including memory T cells are dynamic processes driven by environmental signals. Here, we briefly review the current knowledge of how epigenetic regulation contributes to subset specification, differentiation and memory development in T cells. Specifically, we focus on epigenetic mechanisms differentially active in the two distinct T cell populations expressing αβ or γδ T cell receptors. We also discuss examples of epigenetic alterations of T cells in autoimmune diseases. DNA methylation and histone acetylation are subject to modification by several classes of 'epigenetic modifiers', some of which are in clinical use or in preclinical development. Therefore, we address the impact of some epigenetic modifiers on T-cell activation and differentiation, and discuss possible synergies with T cell-based immunotherapeutic strategies. © 2017 The Foundation for the Scandinavian Journal of Immunology.
Mann, Derek A
Epigenetics is a term that encompasses a variety of regulatory processes that are able to crosstalk in order to influence gene expression and cell phenotype in response to environmental cues. A deep understanding of epigenetics offers the potential for fresh insights into the basis for complex chronic diseases and improved diagnostic and prognostic tools. Moreover, as epigenetic modifications are highly plastic and responsive to the environment, there is much excitement around the theme of epigenetic therapeutics, including not only new drugs but also more informed patient advice on lifestyle choices and their impact on pathology. This review briefly explains the molecular nature of the individual regulatory process that constitute epigenetics, including DNA methylation, histone modifications, chromatin remodeling, transcriptional control, and noncoding RNAs. The ways in which these epigenetic mechanisms influence liver physiology and disease will be considered in detail, particularly in the context of cancer, fibrosis, and nonalcoholic steatohepatitis. The current limitations associated with epigenetic profiling and therapeutics in liver disease are discussed, as is the intriguing possibility that environmental-induced epigenetic changes may become stable and heritable. The aim of the review is to inform hepatologists of the emerging key epigenetic ideas of relevance to liver diseases that are highly likely to form a component of patient management and care in the next decade. Copyright © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.
Full Text Available All mature blood cells derive from hematopoietic stem cells (HSCs through gradual restriction of their cell fate potential and acquisition of specialized functions. Lineage specification and cell commitment require the establishment of specific transcriptional programs involving the activation of lineage-specific genes and the repression of lineage-inappropriate genes. This process requires the concerted action of transcription factors (TFs and epigenetic modifying enzymes. Within the hematopoietic system, B lymphopoiesis is one of the most-studied differentiation programs. Loss of function studies allowed the identification of many TFs and epigenetic modifiers required for B cell development. The usage of systematic analytical techniques such as transcriptome determination, genome-wide mapping of TF binding and epigenetic modifications and mass spectrometry analyses, allowed to gain a systemic description of the intricate networks that guide B cell development. However, the precise mechanisms governing the interaction between TFs and chromatin are still unclear. Generally, chromatin structure can be remodeled by some TFs but in turn can also regulate (i.e. prevent or promote the binding of other TFs. This conundrum leads to the crucial questions of who is on first, when and how. We review here the current knowledge about TF networks and epigenetic regulation during hematopoiesis, with an emphasis on B cell development, and discuss in particular the current models about the interplay between chromatin and transcription factors.
Woods, Brittany A; Levine, Ross L
Over the past decade, genomic studies have identified a number of novel and recurrent somatic mutations that affect epigenetic patterning in patients with myeloid malignancies, including myeloproliferative neoplasms, myelodysplastic syndrome, and acute myeloid leukemia. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells. Subsequent genetic and functional studies have revealed that these mutations affect epigenetic patterning in myeloid diseases. In this review, we discuss historical and recent studies implicating epigenetic modifiers in the development and evolution of the various myeloid malignancies and discuss how this knowledge has and will lead to future clinical and biologic insights. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Lauria, Massimiliano; Rossi, Vincenzo
In eukaryotes, including plants, the genome is compacted into chromatin, which forms a physical barrier for gene transcription. Therefore, mechanisms that alter chromatin structure play an essential role in gene regulation. When changes in the chromatin states are inherited trough mitotic or meiotic cell division, the mechanisms responsible for these changes are defined as epigenetic. In this paper, we review data arising from genome-wide analysis of the epigenetic landscapes in different plant species to establish the correlation between specific epigenetic marks and transcription. In the subsequent sections, mechanisms of epigenetic control of gene regulation mediated by DNA-binding transcription factors and by transposons located in proximity to genes are illustrated. Finally, plant peculiarities for epigenetic control of gene regulation and future perspectives in this research area are discussed. This article is part of a Special Issue entitled: Epigenetic Control of cellular and developmental processes in plants. Copyright © 2011 Elsevier B.V. All rights reserved.
Edward E Large
Full Text Available Evolutionary life history theory seeks to explain how reproductive and survival traits are shaped by selection through allocations of an individual's resources to competing life functions. Although life-history traits evolve rapidly, little is known about the genetic and cellular mechanisms that control and couple these tradeoffs. Here, we find that two laboratory-adapted strains of C. elegans descended from a single common ancestor that lived in the 1950s have differences in a number of life-history traits, including reproductive timing, lifespan, dauer formation, growth rate, and offspring number. We identified a quantitative trait locus (QTL of large effect that controls 24%-75% of the total trait variance in reproductive timing at various timepoints. Using CRISPR/Cas9-induced genome editing, we show this QTL is due in part to a 60 bp deletion in the 3' end of the nurf-1 gene, which is orthologous to the human gene encoding the BPTF component of the NURF chromatin remodeling complex. Besides reproduction, nurf-1 also regulates growth rate, lifespan, and dauer formation. The fitness consequences of this deletion are environment specific-it increases fitness in the growth conditions where it was fixed but decreases fitness in alternative laboratory growth conditions. We propose that chromatin remodeling, acting through nurf-1, is a pleiotropic regulator of life history trade-offs underlying the evolution of multiple traits across different species.
Large, Edward E; Xu, Wen; Zhao, Yuehui; Brady, Shannon C; Long, Lijiang; Butcher, Rebecca A; Andersen, Erik C; McGrath, Patrick T
Evolutionary life history theory seeks to explain how reproductive and survival traits are shaped by selection through allocations of an individual's resources to competing life functions. Although life-history traits evolve rapidly, little is known about the genetic and cellular mechanisms that control and couple these tradeoffs. Here, we find that two laboratory-adapted strains of C. elegans descended from a single common ancestor that lived in the 1950s have differences in a number of life-history traits, including reproductive timing, lifespan, dauer formation, growth rate, and offspring number. We identified a quantitative trait locus (QTL) of large effect that controls 24%-75% of the total trait variance in reproductive timing at various timepoints. Using CRISPR/Cas9-induced genome editing, we show this QTL is due in part to a 60 bp deletion in the 3' end of the nurf-1 gene, which is orthologous to the human gene encoding the BPTF component of the NURF chromatin remodeling complex. Besides reproduction, nurf-1 also regulates growth rate, lifespan, and dauer formation. The fitness consequences of this deletion are environment specific-it increases fitness in the growth conditions where it was fixed but decreases fitness in alternative laboratory growth conditions. We propose that chromatin remodeling, acting through nurf-1, is a pleiotropic regulator of life history trade-offs underlying the evolution of multiple traits across different species.
Oksuz, Ozgur; Tee, Wee-Wei
Chromatin immunoprecipitation (ChIP) is a technique used to determine the association of proteins or histone modifications with chromatin regions in living cells or tissues, and is used extensively in the chromatin biology field to study transcriptional and epigenetic mechanisms. Increasing evidence points to an epigenetic coordination of signaling cascades, such as ERK, that regulate key processes in development and disease, revealing novel principles of gene regulation. Here we describe a detailed protocol for performing chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) for probing histone modifications regulated by ERK signaling in mouse ESCs.
Gräff, Johannes; Mansuy, Isabelle M
The epigenetic marking of chromatin provides a ubiquitous means for cells to shape and maintain their identity, and to react to environmental stimuli via specific remodeling. Such an epigenetic code of the core components of chromatin, DNA and histone proteins, can thus be stable but is also highly dynamic. In the nervous system, epigenetic codes are critical for basic cellular processes such as synaptic plasticity, and for complex behaviours such as learning and memory. At the same time, epigenetic marks can be stably transmitted through mitosis and meiosis, and thereby underlie non-genomic transgenerational inheritance of behavioural traits. In this review, we describe recent findings on the role and mechanisms of epigenetic codes in the brain, and discuss their implication in synaptic plasticity, cognitive functions and psychiatric disorders. We provide examples of transgenerational inheritance of epigenetic marks that affect simple morphological traits or complex processes such as disease susceptibility, and point to the potential implication of epigenetic codes in medicine and evolution.
Full Text Available The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Previous analyses in SUM-52 breast cancer cells showed amplification and overexpression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. KAT6A is a histone acetyltransferase previously identified as a fusion partner with CREB binding protein in acute myeloid leukemia. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal. Previous data from our laboratory identified FGFR2 as a driving oncogene in SUM-52 cells. The colony forming efficiency of SUM-52 KAT6A knockdown cells in the presence of FGFR inhibition was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a novel oncogene in breast cancers bearing the 8p11-p12 amplicon. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers.
Tatavosian, Roubina; Ren, Xiaojun
Epigenetic complexes regulate chromatin dynamics via binding to and assembling on chromatin. However, the mechanisms of chromatin binding and assembly of epigenetic complexes within cells remain incompletely understood, partly due to technical challenges. Here, we present a new approach termed single-molecule chromatin immunoprecipitation imaging (Sm-ChIPi) that enables to assess the cellular assembly stoichiometry of epigenetic complexes on chromatin. Sm-ChIPi was developed based on chromatin immunoprecipitation followed by single-molecule fluorescence microscopy imaging. In this method, an epigenetic complex subunit fused with a gene coding for a fluorescent protein is stably expressed in its corresponding knockout cells. Nucleosomes associated with epigenetic complexes are isolated from cells at native conditions and incubated with biotinylated antibodies. The resulting complexes are immobilized on a quartz slide that had been passivated and functionalized with NeutrAvidin. Image stacks are then acquired by using single-molecule TIRF microscopy. The individual spots imaged by TIRF microscopy represent single protein-nucleosome complexes. The number of copies of the protein complexes on a nucleosome is inferred from the fluorescence photobleaching measurements. Sm-ChIPi is a sensitive and direct method that can quantify the cellular assembly stoichiometry of epigenetic complexes on chromatin.
Chacon, Jessica Ann; Schutsky, Keith; Powell, Daniel J
Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.
Lynch, Tim J; Erickson, B Joy; Miller, Dusty R; Finkelstein, Ruth R
Overexpression of ABI5/ABF binding proteins (AFPs) results in extreme ABA resistance of seeds via multiple mechanisms repressing ABA response, including interactions with histone deacetylases and the co-repressor TOPLESS. Several ABI5/ABF binding proteins (AFPs) inhibit ABA response, resulting in extreme ABA resistance in transgenic Arabidopsis overexpression lines, but their mechanism of action has remained obscure. By analogy to the related Novel Interactor of JAZ (NINJA) protein, it was suggested that the AFPs interact with the co-repressor TOPLESS to inhibit ABA-regulated gene expression. This study shows that the AFPs that inhibit ABA response have intrinsic repressor activity in a heterologous system, which does not depend on the domain involved in the interaction with TOPLESS. This domain is also not essential for repressing ABA response in transgenic plants, but does contribute to stronger ABA resistance. Additional interactions between some AFPs and histone deacetylase subunits were observed in yeast two-hybrid and bimolecular fluorescence assays, consistent with a more direct mechanism of AFP-mediated repression of gene expression. Chemical inhibition of histone deacetylase activity by trichostatin A suppressed AFP effects on a small fraction of the ABI5-regulated genes tested. Collectively, these results suggest that the AFPs participate in multiple mechanisms modulating ABA response, including both TOPLESS-dependent and -independent chromatin modification.
The genetic code cannot alone explain the diversity of cellular and individual phenotypes. Epigenetics provides an additional level of information that is not encoded in the DNA molecule but nonetheless influences its activity in a stable and heritable manner through cell divisions. This effect on gene expression results from variations in chromatin states and is induced by biochemical modifications targeting the DNA molecule or associated histone proteins. Epigenetic regulation can convert a developmental or transient environmental signal into a stable transcriptional response, which will then be perpetuated even in the absence of the original stimulus. Epigenetic regulation explains how, starting from a unique genome, the pluripotent embryo can generate a variety of tissues and maintain their identity throughout development. Epigenetics has a broad impact on development, by controlling pluripotent and differentiated states. An increasing number of pathological situations are being attributed to abnormal establishment or maintenance of epigenetic patterns. Given the mitotic heritability of epigenetic states, a key question is whether epigenetic information can also be transmitted through generations.
01/0005-0011. Keywords. Aging; chromatin; epigenetics; histones. Author Affiliations. Navneet K Matharu1 Rakesh K Mishra1. Centre for Cellular and Molecular Biology, CSIR Hyderabad 500 007, India. Dates. Early published: 14 March 2011 ...
Jerónimo, Carmen; Bastian, Patrick J; Bjartell, Anders; Carbone, Giuseppina M; Catto, James W F; Clark, Susan J; Henrique, Rui; Nelson, William G; Shariat, Shahrokh F
Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Durinck, Kaat; Speleman, Frank
In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB.
Ana Paula Santos
Full Text Available The spatial organization of chromosome structure within the interphase nucleus, as well as the patterns of methylome and histone modifications, represent intersecting layers that influence genome accessibility and function. This review is focused on the plastic nature of chromatin structure and epigenetic marks in association to stress situations. The use of chemical compounds (epigenetic drugs or T-DNA-mediated mutagenesis affecting epigenetic regulators (epi-mutants are discussed as being important tools for studying the impact of deregulated epigenetic backgrounds on gene function and phenotype. The inheritability of epigenetic marks and chromatin configurations along successive generations are interpreted as a way for plants to “communicate” past experiences of stress sensing. A mechanistic understanding of chromatin and epigenetics plasticity in plant response to stress, including tissue- and genotype-specific epigenetic patterns, may help to reveal the epigenetics contributions for genome and phenotype regulation.
Mathews, Herbert L; Janusek, Linda Witek
In this Introduction to the Named Series "Epigenetics, Brain, Behavior, and Immunity" an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome. Copyright © 2010 Elsevier Inc. All rights reserved.
Mathews, Herbert L.; Janusek, Linda Witek
In this Introduction to the Named Series “Epigenetics, Brain, Behavior, and Immunity” an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin remodeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome. PMID:20832468
In eukaryotes, most of the DNA is located in the nucleus where it is organized with histone proteins in a higher order structure as chromatin. Chromatin and chromatin-associated proteins contribute to DNA-related processes such as replication and transcription as well as epigenetic regulation. Protein functions are often regulated by PTMs among which phosphorylation is one of the most abundant PTM. Phosphorylation of proteins affects important properties, such as enzyme activity, protein stability, or subcellular localization. We here describe the main specificities of protein phosphorylation in plants and review the current knowledge on phosphorylation-dependent regulation of plant chromatin and chromatin-associated proteins. We also outline some future challenges to further elucidate protein phosphorylation and chromatin regulation.
Stefanska, Barbara; MacEwan, David J
Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity ‘beyond’ simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered – it is pharmacology that will have to keep pace. PMID:25966315
Stefanska, Barbara; MacEwan, David J
Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity 'beyond' simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered - it is pharmacology that will have to keep pace. © 2015 The British Pharmacological Society.
genomic material can show quiet diverse phenotypes characterized by organ speci c gene expression patterns. The mechanisms responsible for this phenotypic plasticity are characterized as epigenetic, as they in ict their e ect \\epi-" (Greek for \\above" or \\on top") of the genetic code. For a gene...... regulatory mechanism to be classi ed as epigenetic, it is required that it is self-sustainable in the sense that the governed gene expression or repression should prevail for the lifetime of the cell and must be inherited by possible daughter cells. An example of epigenetic di erentiation is the bistable...... the DNA into chromatin structures. Once established the patterns may be conserved over many cell generations. The self-sustainable nature of the patterns is attributed to the cis-acting mechanism of read-write enzymes that facilitates the same histone modi cations as they recognize. Developing olfactory...
Goel, Ajay; Boland, C Richard
In the early years of the molecular biology revolution, cancer research was mainly focused on genetic changes (ie, those that altered DNA sequences). Although this has been extremely useful as our understanding of the pathogenesis and biology of cancer has grown and matured, there is another realm in tumor development that does not involve changing the sequence of cellular DNA. This field is called "epigenetics" and broadly encompasses changes in the methylation of cytosines in DNA, changes in histone and chromatin structure, and alterations in the expression of microRNAs, which control the stability of many messenger RNAs and serve as "master regulators" of gene expression. This review focuses on the epigenetics of colorectal cancer and illustrates the impact epigenetics has had on this field. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
Utilizing next-generation sequencing technology in combination with chromatin immunoprecipitation (ChIP) technology, our study provides systematic and novel insights into the relationships between nutrition and epigenetics. One paradigmatic example of nutrient-epigenetic-phenotype relationship is th...
Gabory, Anne; Attig, Linda; Junien, Claudine
The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli that result in modified gene expression patterns and phenotypes later in life, are a topic of considerable interest. This article focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions, and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects of environmental stressors on a small number of epigenetic marks, at the global or individual gene level, in humans and in animal models. In parallel, increasing numbers of studies based on high-throughput technologies are revealing additional complexity in epigenetic processes by highlighting the importance of crosstalk between different epigenetic marks in humans and mice. A number of studies focusing on metabolic programming and the developmental origin of health and disease have identified links between early nutrition, epigenetic processes, and long-term illness. The existence of a self-propagating epigenetic cycle has been shown. Moreover, recent studies have shown an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, however, we are still far from understanding how, when, and where environmental stressors disturb key epigenetic mechanisms. Thus, the need to identify original key marks and monitor the changes they undergo throughout development, during an individual's lifetime, or over several generations remains a challenging issue.
Bardhan, Kankana; Liu, Kebin, E-mail: Kliu@gru.edu [Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912 (United States)
Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.
Dietz, Kevin N; Di Stefano, Luisa; Maher, Robert C; Zhu, Hui; Macdonald, Marcy E; Gusella, James F; Walker, James A
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG expansion mutation in HTT, the gene encoding huntingtin. Evidence from both human genotype-phenotype relationships and mouse model systems suggests that the mutation acts by dysregulating some normal activity of huntingtin. Recent work in the mouse has revealed a role for huntingtin in epigenetic regulation during development. Here, we examine the role of the Drosophila huntingtin ortholog (dhtt) in chromatin regulation in the development of the fly. Although null dhtt mutants display no overt phenotype, we found that dhtt acts as a suppressor of position-effect variegation (PEV), suggesting that it influences chromatin organization. We demonstrate that dhtt affects heterochromatin spreading in a PEV model by modulating histone H3K9 methylation levels at the heterochromatin-euchromatin boundary. To gain mechanistic insights into how dhtt influences chromatin function, we conducted a candidate genetic screen using RNAi lines targeting known PEV modifier genes. We found that dhtt modifies phenotypes caused by knockdown of a number of key epigenetic regulators, including chromatin-associated proteins, histone demethylases (HDMs) and methyltransferases. Notably, dhtt strongly modifies phenotypes resulting from loss of the HDM dLsd1, in both the ovary and wing, and we demonstrate that dhtt appears to act as a facilitator of dLsd1 function in regulating global histone H3K4 methylation levels. These findings suggest that a fundamental aspect of huntingtin function in heterochromatin/euchromatin organization is evolutionarily conserved across phyla. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Wessam F. El-Hadidy
Conclusion: The present work could provide a proof of concept that procainamide could be used as a possible therapeutic potential in type 2 diabetics as an epigenetic demethylating agent to increase insulin levels and it is better to be used in combination with oral hypoglycemic agent e.g. metformin to decrease insulin resistance.
Jasencakova, Zuzana; Groth, Anja
Cancer cells accumulate widespread local and global chromatin changes and the source of this instability remains a key question. Here we hypothesize that chromatin alterations including unscheduled silencing can arise as a consequence of perturbed histone dynamics in response to replication stress. Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 mono-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor-promoting insults is recognized as a significant source of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis. Copyright © 2010 WILEY Periodicals, Inc.
Braun, Simon M G; Kirkland, Jacob G; Chory, Emma J; Husmann, Dylan; Calarco, Joseph P; Crabtree, Gerald R
Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.
Tekel, Stefan J; Haynes, Karmella A
Chromatin is a system of proteins, RNA, and DNA that interact with each other to organize and regulate genetic information within eukaryotic nuclei. Chromatin proteins carry out essential functions: packing DNA during cell division, partitioning DNA into sub-regions within the nucleus, and controlling levels of gene expression. There is a growing interest in manipulating chromatin dynamics for applications in medicine and agriculture. Progress in this area requires the identification of design rules for the chromatin system. Here, we focus on the relationship between the physical structure and function of chromatin proteins. We discuss key research that has elucidated the intrinsic properties of chromatin proteins and how this information informs design rules for synthetic systems. Recent work demonstrates that chromatin-derived peptide motifs are portable and in some cases can be customized to alter their function. Finally, we present a workflow for fusion protein design and discuss best practices for engineering chromatin to assist scientists in advancing the field of synthetic epigenetics. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Tatavosian, Roubina; Zhen, Chao Yu; Duc, Huy Nguyen; Balas, Maggie M; Johnson, Aaron M; Ren, Xiaojun
Epigenetic complexes play an essential role in regulating chromatin structure, but information about their assembly stoichiometry on chromatin within cells is poorly understood. The cellular assembly stoichiometry is critical for appreciating the initiation, propagation, and maintenance of epigenetic inheritance during normal development and in cancer. By combining genetic engineering, chromatin biochemistry, and single-molecule fluorescence imaging, we developed a novel and sensitive approach termed single-molecule chromatin immunoprecipitation imaging (Sm-ChIPi) to enable investigation of the cellular assembly stoichiometry of epigenetic complexes on chromatin. Sm-ChIPi was validated by using chromatin complexes with known stoichiometry. The stoichiometry of subunits within a polycomb complex and the assembly stoichiometry of polycomb complexes on chromatin have been extensively studied but reached divergent views. Moreover, the cellular assembly stoichiometry of polycomb complexes on chromatin remains unexplored. Using Sm-ChIPi, we demonstrated that within mouse embryonic stem cells, one polycomb repressive complex (PRC) 1 associates with multiple nucleosomes, whereas two PRC2s can bind to a single nucleosome. Furthermore, we obtained direct physical evidence that the nucleoplasmic PRC1 is monomeric, whereas PRC2 can dimerize in the nucleoplasm. We showed that ES cell differentiation induces selective alteration of the assembly stoichiometry of Cbx2 on chromatin but not other PRC1 components. We additionally showed that the PRC2-mediated trimethylation of H3K27 is not required for the assembly stoichiometry of PRC1 on chromatin. Thus, these findings uncover that PRC1 and PRC2 employ distinct mechanisms to assemble on chromatin, and the novel Sm-ChIPi technique could provide single-molecule insight into other epigenetic complexes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Tatavosian, Roubina; Zhen, Chao Yu; Duc, Huy Nguyen; Balas, Maggie M.; Johnson, Aaron M.; Ren, Xiaojun
Epigenetic complexes play an essential role in regulating chromatin structure, but information about their assembly stoichiometry on chromatin within cells is poorly understood. The cellular assembly stoichiometry is critical for appreciating the initiation, propagation, and maintenance of epigenetic inheritance during normal development and in cancer. By combining genetic engineering, chromatin biochemistry, and single-molecule fluorescence imaging, we developed a novel and sensitive approach termed single-molecule chromatin immunoprecipitation imaging (Sm-ChIPi) to enable investigation of the cellular assembly stoichiometry of epigenetic complexes on chromatin. Sm-ChIPi was validated by using chromatin complexes with known stoichiometry. The stoichiometry of subunits within a polycomb complex and the assembly stoichiometry of polycomb complexes on chromatin have been extensively studied but reached divergent views. Moreover, the cellular assembly stoichiometry of polycomb complexes on chromatin remains unexplored. Using Sm-ChIPi, we demonstrated that within mouse embryonic stem cells, one polycomb repressive complex (PRC) 1 associates with multiple nucleosomes, whereas two PRC2s can bind to a single nucleosome. Furthermore, we obtained direct physical evidence that the nucleoplasmic PRC1 is monomeric, whereas PRC2 can dimerize in the nucleoplasm. We showed that ES cell differentiation induces selective alteration of the assembly stoichiometry of Cbx2 on chromatin but not other PRC1 components. We additionally showed that the PRC2-mediated trimethylation of H3K27 is not required for the assembly stoichiometry of PRC1 on chromatin. Thus, these findings uncover that PRC1 and PRC2 employ distinct mechanisms to assemble on chromatin, and the novel Sm-ChIPi technique could provide single-molecule insight into other epigenetic complexes. PMID:26381410
Jullien, Jerome; Vodnala, Munender; Pasque, Vincent; Oikawa, Mami; Miyamoto, Kei; Allen, George; David, Sarah Anne; Brochard, Vincent; Wang, Stan; Bradshaw, Charles; Koseki, Haruhiko; Sartorelli, Vittorio; Beaujean, Nathalie; Gurdon, John
Understanding the mechanism of resistance of genes to reactivation will help improve the success of nuclear reprogramming. Using mouse embryonic fibroblast nuclei with normal or reduced DNA methylation in combination with chromatin modifiers able to erase H3K9me3, H3K27me3, and H2AK119ub1 from transplanted nuclei, we reveal the basis for resistance of genes to transcriptional reprogramming by oocyte factors. A majority of genes is affected by more than one type of treatment, suggesting that resistance can require repression through multiple epigenetic mechanisms. We classify resistant genes according to their sensitivity to 11 chromatin modifier combinations, revealing the existence of synergistic as well as adverse effects of chromatin modifiers on removal of resistance. We further demonstrate that the chromatin modifier USP21 reduces resistance through its H2AK119 deubiquitylation activity. Finally, we provide evidence that H2A ubiquitylation also contributes to resistance to transcriptional reprogramming in mouse nuclear transfer embryos. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Full Text Available Classic “position-effect” experiments repositioned genes near telomeres to demonstrate that the epigenetic landscape can dramatically alter gene expression. Here, we show that systematic gene knockout collections provide an exceptional resource for interrogating position effects, not only near telomeres but at every genetic locus. Because a single reporter gene replaces each deleted gene, interrogating this reporter provides a sensitive probe into different chromatin environments while controlling for genetic context. Using this approach, we find that, whereas systematic replacement of yeast genes with the kanMX marker does not perturb the chromatin landscape, chromatin differences associated with gene position account for 35% of kanMX activity. We observe distinct chromatin influences, including a Set2/Rpd3-mediated antagonistic interaction between histone H3 lysine 36 trimethylation and the Rap1 transcriptional activation site in kanMX. This interaction explains why some yeast genes have been resistant to deletion and allows successful generation of these deletion strains through the use of a modified transformation procedure. These findings demonstrate that chromatin regulation is not governed by a uniform “histone code” but by specific interactions between chromatin and genetic factors.
Bartke, Till; Borgel, Julie; DiMaggio, Peter A
The involvement of epigenetic processes in the origin and progression of cancer is now widely appreciated. Consequently, targeting the enzymatic machinery that controls the epigenetic regulation of the genome has emerged as an attractive new strategy for therapeutic intervention. The development of epigenetic drugs requires a detailed knowledge of the processes that govern chromatin regulation. Over the recent years, mass spectrometry (MS) has become an indispensable tool in epigenetics research. In this review, we will give an overview of the applications of MS-based proteomics in studying various aspects of chromatin biology. We will focus on the use of MS in the discovery and mapping of histone modifications and how novel proteomic approaches are being utilized to identify and study chromatin-associated proteins and multi-subunit complexes. Finally, we will discuss the application of proteomic methods in the diagnosis and prognosis of cancer based on epigenetic biomarkers and comment on their future impact on cancer epigenetics.
Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech
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
Irianto, Jerome; Lee, David A; Knight, Martin M
The level of chromatin condensation is related to the silencing/activation of chromosomal territories and therefore impacts on gene expression. Chromatin condensation changes during cell cycle, progression and differentiation, and is influenced by various physicochemical and epigenetic factors. This study describes a validated experimental technique to quantify chromatin condensation. A novel image processing procedure is developed using Sobel edge detection to quantify the level of chromatin condensation from nuclei images taken by confocal microscopy. The algorithm was developed in MATLAB and used to quantify different levels of chromatin condensation in chondrocyte nuclei achieved through alteration in osmotic pressure. The resulting chromatin condensation parameter (CCP) is in good agreement with independent multi-observer qualitative visual assessment. This image processing technique thereby provides a validated unbiased parameter for rapid and highly reproducible quantification of the level of chromatin condensation. Copyright © 2013 IPEM. Published by Elsevier Ltd. All rights reserved.
Bheda, Poonam; Schneider, Robert
Mechanistically, how epigenetic states are inherited through cellular divisions remains an important open question in the chromatin field and beyond. Defining the heritability of epigenetic states and the underlying chromatin-based mechanisms within a population of cells is complicated due to cell heterogeneity combined with varying levels of stability of these states; thus, efforts must be focused toward single-cell analyses. The approaches presented here constitute the forefront of epigenetics research at the single-cell level using classic and innovative methods to dissect epigenetics mechanisms from the limited material available in a single cell. This review further outlines exciting future avenues of research to address the significance of epigenetic heterogeneity and the contributions of microfluidics technologies to single-cell isolation and analysis. Copyright © 2014 Elsevier Ltd. All rights reserved.
Hershkovitz, M; Riggs, A D
Chromatin structure is becoming increasingly recognized as important for a full understanding of gene function and cell memory. With regard to cell memory, which involves the transfer of chromatin-encoded epigenetic information from one cell generation to another, the detailed structure of metaphase chromatin is of crucial importance. In this paper we describe methods for the use of dimethyl sulfate, DNase I, and potassium permanganate for in vivo footprinting and chromatin analysis, with special emphasis on studies of metaphase cells. We review the use of ligation-mediated PCR for the analysis of chromatin, including the human phosphoglycerate kinase promoter, and also report initial studies of a matrix attachment region near the human beta-interferon gene.
Fork, Christian; Gu, Lunda; Hitzel, Juliane
OBJECTIVE: Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. APPROACH AND RESULTS...... outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C...
Szarc vel Szic, Katarzyna; Ndlovu, Matladi N; Haegeman, Guy; Vanden Berghe, Wim
Numerous clinical, physiopathological and epidemiological studies have underlined the detrimental or beneficial role of nutritional factors in complex inflammation related disorders such as allergy, asthma, obesity, type 2 diabetes, cardiovascular disease, rheumatoid arthritis and cancer. Today, nutritional research has shifted from alleviating nutrient deficiencies to chronic disease prevention. It is known that lifestyle, environmental conditions and nutritional compounds influence gene expression. Gene expression states are set by transcriptional activators and repressors and are often locked in by cell-heritable chromatin states. Only recently, it has been observed that the environmental conditions and daily diet can affect transgenerational gene expression via "reversible" heritable epigenetic mechanisms. Epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or corrupt chromatin states of key inflammatory genes and noncoding RNAs, recently emerged as major governing factors in cancer, chronic inflammatory and metabolic disorders. Reciprocally, inflammation, metabolic stress and diet composition can also change activities of the epigenetic machinery and indirectly or directly change chromatin marks. This has recently launched re-exploration of anti-inflammatory bioactive food components for characterization of their effects on epigenome modifying enzymatic activities (acetylation, methylation, phosphorylation, ribosylation, oxidation, ubiquitination, sumoylation). This may allow to improve healthy aging by reversing disease prone epimutations involved in chronic inflammatory and metabolic disorders. Copyright © 2010 Elsevier Inc. All rights reserved.
Conn, Kristen L.; Schang, Luis M.
Latent HSV-1 genomes are chromatinized with silencing marks. Since 2004, however, there has been an apparent inconsistency in the studies of the chromatinization of the HSV-1 genomes in lytically infected cells. Nuclease protection and chromatin immunoprecipitation assays suggested that the genomes were not regularly chromatinized, having only low histone occupancy. However, the chromatin modifications associated with transcribed and non-transcribed HSV-1 genes were those associated with active or repressed transcription, respectively. Moreover, the three critical HSV-1 transcriptional activators all had the capability to induce chromatin remodelling, and interacted with critical chromatin modifying enzymes. Depletion or overexpression of some, but not all, chromatin modifying proteins affected HSV-1 transcription, but often in unexpected manners. Since 2010, it has become clear that both cellular and HSV-1 chromatins are highly dynamic in infected cells. These dynamics reconcile the weak interactions between HSV-1 genomes and chromatin proteins, detected by nuclease protection and chromatin immunoprecipitation, with the proposed regulation of HSV-1 gene expression by chromatin, supported by the marks in the chromatin in the viral genomes and the abilities of the HSV-1 transcription activators to modulate chromatin. It also explains the sometimes unexpected results of interventions to modulate chromatin remodelling activities in infected cells. PMID:23863878
Rodenhiser, David I; Bérubé, Nathalie G; Mann, Mellissa R W
In May 2011, the Canadian Conference on Epigenetics: Epigenetics Eh! was held in London, Canada. The objectives of this conference were to showcase the breadth of epigenetic research on environment and health across Canada and to provide the catalyst to develop collaborative Canadian epigenetic research opportunities, similar to existing international epigenetic initiatives in the US and Europe. With ten platform sessions and two sessions with over 100 poster presentations, this conference featured cutting-edge epigenetic research, presented by Canadian and international principal investigators and their trainees in the field of epigenetics and chromatin dynamics. An EpigenART competition included ten artists, creating a unique opportunity for artists and scientists to interact and explore their individual interpretations of this scientific discipline. The conference provided a unique venue for a significant cross-section of Canadian epigenetic researchers from diverse disciplines to meet, interact, collaborate and strategize at the national level.
Full Text Available Modifications on specific histone residues and DNA methylation play an essential role in lineage choice and cellular reprogramming. We have previously shown that histone modifications or combinatorial codes of transcription factors (TFs are critical for the differentiation of multipotential progenitors into myelinating oligodendrocytes. In this study we asked whether combining global manipulation of DNA methylation and histone acetylation together with the expression of oligodendrocyte-specific TFs, was sufficient to switch the identity of fibroblasts into myelin gene-expressing cells.Transfection of six oligodendrocyte-specific TFs (Olig1, Olig2, Sox10, Mash1, E47 and Nkx2.2 into NIH3T3 fibroblasts was capable of inducing expression of myelin gene promoter-driven reporters, but did not activate endogenous myelin gene expression. These results suggested the existence of a transcriptionally incompetent chromatin conformation in NIH3T3 fibroblasts. Using chromatin immunoprecipitation (ChIP analysis, we compared the histone code on the conserved regions of myelin genes (i.e. Mbp and Mag in differentiating oligodendrocyte progenitors and NIH3T3 fibroblasts. Chromatin at myelin gene loci was characterized by the presence of repressive histone modifications (me3K9H3 and me3K27H3 in NIH3T3 fibroblasts and active histone marks (me3K4H3 and AcH3 in oligodendrocyte lineage cells. To induce a transcriptionally competent chromatin signature, NIH3T3 fibroblasts were treated with 5-azadeoxy-citidine (5-AzaC to decrease DNA methylation, and trichostatin A (TSA or sirtinol, to favor histone acetylation. Treatment with 5-AzaC/TSA but not sirtinol, resulted in the detection of endogenous myelin gene transcripts in fibroblasts, although not to the levels detected in myelinating cells. Transfection of oligodendrocyte-specific TFs after 5-AzaC/TSA treatment did not further increase myelin gene expression, nor did it reprogram the transcriptional network of NIH3T3
Zhou, Jian; Troyanskaya, Olga G.
Interpreting the functional state of chromatin from the combinatorial binding patterns of chromatin factors, that is, the chromatin codes, is crucial for decoding the epigenetic state of the cell. Here we present a systematic map of Drosophila chromatin states derived from data-driven probabilistic modelling of dependencies between chromatin factors. Our model not only recapitulates enhancer-like chromatin states as indicated by widely used enhancer marks but also divides these states into three functionally distinct groups, of which only one specific group possesses active enhancer activity. Moreover, we discover a strong association between one specific enhancer state and RNA Polymerase II pausing, linking transcription regulatory potential and chromatin organization. We also observe that with the exception of long-intron genes, chromatin state transition positions in transcriptionally active genes align with an absolute distance to their corresponding transcription start site, regardless of gene length. Using our method, we provide a resource that helps elucidate the functional and spatial organization of the chromatin code landscape. PMID:26841971
Baccarelli, Andrea; Bollati, Valentina
Epigenetics investigates heritable changes in gene expression occurring without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, can change genome function under exogenous influence. Here, we review current evidence indicating that epigenetic alterations mediate toxicity from environmental chemicals. In-vitro, animal, and human investigations have identified several classes of environmental chemicals that modify epigenetic marks, including metals (cadmium, arsenic, nickel, chromium, and methylmercury), peroxisome proliferators (trichloroethylene, dichloroacetic acid, and TCA), air pollutants (particulate matter, black carbon, and benzene), and endocrine-disrupting/reproductive toxicants (diethylstilbestrol, bisphenol A, persistent organic pollutants, and dioxin). Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied environmental chemicals in relation to histone modifications and microRNA. For several exposures, it has been proved that chemicals can alter epigenetic marks, and that the same or similar epigenetic alterations can be found in patients with the disease of concern or in diseased tissues. Future prospective investigations are needed to determine whether exposed individuals develop epigenetic alterations over time and, in turn, which such alterations increase the risk of disease. Also, further research is needed to determine whether environmental epigenetic changes are transmitted transgenerationally.
Collotta, M; Bertazzi, P A; Bollati, V
Pesticides, a wide class of environmental contaminants, may cause both acute and delayed health effects in exposed subjects. These effects can range from simple irritation of the skin and eyes to more severe effects such as affecting the nervous system, the reproductive system and cancer. The molecular mechanisms underlying such effects are still under investigation. Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications and microRNA expression, can be triggered by environmental factors. We review current evidences indicating that epigenetic modifications may mediate pesticide effects on human health. In vitro, animal, and human investigations have identified several classes of pesticides that modify epigenetic marks, including endocrine disruptors, persistent organic pollutants, arsenic, several herbicides and insecticides. Several investigations have examined the effects of environmental exposures and epigenetic markers, and identified toxicants that modify epigenetic states. These modifications are similar to the ones found in pathological tissue samples. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of pesticides health effects, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Bertrand R. Caré
Full Text Available In eukaryotes, chromatin is coated with epigenetic marks which induce differential gene expression profiles and eventually lead to different cellular phenotypes. One of the challenges of contemporary cell biology is to relate the wealth of epigenomic data with the observed physical properties of chromatin. In this study, we present a polymer physics framework that takes into account the sizes of epigenomic domains. We build a model of chromatin as a block copolymer made of domains with various sizes. This model produces a rich set of conformations which is well explained by finite-size scaling analysis of the coil-globule transition of epigenomic domains. Our results suggest that size-dependent folding of epigenomic domains may be a crucial physical mechanism able to provide chromatin with tissue-specific folding states, these being associated with differential gene expression.
van der Heijden, Charlotte D C C; Noz, Marlies P; Joosten, Leo A B; Netea, Mihai G; Riksen, Niels P; Keating, Samuel T
A growing body of clinical and experimental evidence has challenged the traditional understanding that only the adaptive immune system can mount immunological memory. Recent findings describe the adaptive characteristics of the innate immune system, underscored by its ability to remember antecedent foreign encounters and respond in a nonspecific sensitized manner to reinfection. This has been termed trained innate immunity. Although beneficial in the context of recurrent infections, this might actually contribute to chronic immune-mediated diseases, such as atherosclerosis. Recent Advances: In line with its proposed role in sustaining cellular memories, epigenetic reprogramming has emerged as a critical determinant of trained immunity. Recent technological and computational advances that improve unbiased acquisition of epigenomic profiles have significantly enhanced our appreciation for the complexities of chromatin architecture in the contexts of diverse immunological challenges. Key to resolving the distinct chromatin signatures of innate immune memory is a comprehensive understanding of the precise physiological targets of regulatory proteins that recognize, deposit, and remove chemical modifications from chromatin as well as other gene-regulating factors. Drawing from a rapidly expanding compendium of experimental and clinical studies, this review details a current perspective of the epigenetic pathways that support the adapted phenotypes of monocytes and macrophages. We explore future strategies that are aimed at exploiting the mechanism of trained immunity to improve the prevention and treatment of infections and immune-mediated chronic disorders. Antioxid. Redox Signal. 00, 000-000.
Epigenetics is an important mechanism of gene regulation that is dependent on the chromatin structure, which is determined by the epigenetic chemical modification of DNA and histone proteins. It is known that the failure of epigenetic mechanisms causes congenital neurodevelopmental disorders (NDs), and that early life exposure to mental stress and endocrine disrupting chemicals, such as phthalates, bisphenol A, and tobacco, can change epigenetic mechanism and gene expression in the brain and cause NDs. Moreover, environmentally induced epigenetic changes are not erased during gametogenesis and are transmitted to subsequent generations, leading to changes in behavior phenotypes. However, epigenetics has a reversible nature because it is based on the addition or removal of chemical residues, and thus the original epigenetic status may be restored. Indeed, several drugs used for mental disorders and NDs restore the epigenetic state and gene expression. Improved epigenetic understanding of NDs will provide important clues for the development of new drugs that take advantage of epigenetic reversibility.
Lim, Jana P.; Brunet, Anne
It is textbook knowledge that inheritance of traits is governed by genetics, and that the epigenetic modifications an organism acquires are reset between generations. Recently, however, transgenerational epigenetic inheritance has emerged as a rapidly growing field, providing evidence suggesting that some epigenetic changes may result in persistent phenotypes across generations. Here, we survey some of the most recent examples of transgenerational epigenetic inheritance in animals, ranging from C. elegans to humans, and describe approaches and limitations to studying this phenomenon. We also review the current body of evidence implicating chromatin modifications and RNA molecules in mechanisms underlying this unconventional mode of inheritance and discuss its evolutionary implications. PMID:23410786
Dawson, Mark A; Kouzarides, Tony
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer. Copyright © 2012 Elsevier Inc. All rights reserved.
Singh, Usha; Malik, Manzoor Ahmad; Goswami, Sandeep; Shukla, Swati; Kaur, Jasbir
Retinoblastoma is a rare type of eye cancer of the retina that commonly occurs in early childhood and mostly affects the children before the age of 5. It occurs due to the mutations in the retinoblastoma gene (RB1) which inactivates both alleles of the RB1. RB1 was first identified as a tumor suppressor gene, which regulates cell cycle components and associated with retinoblastoma. Previously, genetic alteration was known as the major cause of its occurrence, but later, it is revealed that besides genetic changes, epigenetic changes also play a significant role in the disease. Initiation and progression of retinoblastoma could be due to independent or combined genetic and epigenetic events. Remarkable work has been done in understanding retinoblastoma pathogenesis in terms of genetic alterations, but not much in the context of epigenetic modification. Epigenetic modifications that silence tumor suppressor genes and activate oncogenes include DNA methylation, chromatin remodeling, histone modification and noncoding RNA-mediated gene silencing. Epigenetic changes can lead to altered gene function and transform normal cell into tumor cells. This review focuses on important epigenetic alteration which occurs in retinoblastoma and its current state of knowledge. The critical role of epigenetic regulation in retinoblastoma is now an emerging area, and better understanding of epigenetic changes in retinoblastoma will open the door for future therapy and diagnosis.
Wu, William Kk; Yu, Jun; Chan, Matthew Tv; To, Ka F; Cheng, Alfred Sl
Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling and microRNAs, convert environmental signals to transcriptional outputs but are commonly hijacked by pathogenic microorganisms. Recent advances in cancer epigenomics have shed new light on the importance of epigenetic deregulation in Helicobacter pylori- and Epstein-Barr virus (EBV)-driven gastric tumourigenesis. Moreover, it is becoming apparent that epigenetic mechanisms interact through crosstalk and feedback loops, which modify global gene expression patterns. The SWI/SNF remodelling complexes are commonly involved in gastric cancers associated with H. pylori or EBV through different mechanisms, including microRNA-mediated deregulation and genetic mutations. While H. pylori causes epigenetic silencing of tumour-suppressor genes to deregulate cellular pathways, EBV-positive tumours exhibit a widespread and distinctive DNA hypermethylation profile. Given the early successes of epigenetic drugs in haematological malignancies, further studies are mandated to enrich and translate our understanding of combinatorial epigenetic deregulation in gastric cancers into interventional strategies in the clinic. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Yaish, Mahmoud W; Colasanti, Joseph; Rothstein, Steven J
Plants interact with their environment by modifying gene expression patterns. One mechanism for this interaction involves epigenetic modifications that affect a number of aspects of plant growth and development. Thus, the epigenome is highly dynamic in response to environmental cues and developmental changes. Flowering is controlled by a set of genes that are affected by environmental conditions through an alteration in their expression pattern. This ensures the production of flowers even when plants are growing under adverse conditions, and thereby enhances transgenerational seed production. In this review recent findings on the epigenetic changes associated with flowering in Arabidopsis thaliana grown under abiotic stress conditions such as cold, drought, and high salinity are discussed. These epigenetic modifications include DNA methylation, histone modifications, and the production of micro RNAs (miRNAs) that mediate epigenetic modifications. The roles played by the phytohormones abscisic acid (ABA) and auxin in chromatin remodelling are also discussed. It is shown that there is a crucial relationship between the epigenetic modifications associated with floral initiation and development and modifications associated with stress tolerance. This relationship is demonstrated by the common epigenetic pathways through which plants control both flowering and stress tolerance, and can be used to identify new epigenomic players.
Olivier-Van Stichelen, Stéphanie; Hanover, John A
The O-linked N-acetylglucosamine (O-GlcNAc) modification is both responsive to nutrient availability and capable of altering intracellular cellular signalling. We summarize data defining a role for O-GlcNAcylation in metabolic homeostasis and epigenetic regulation of development in the intrauterine environment. O-GlcNAc transferase (OGT) catalyzes nutrient-driven O-GlcNAc addition and is subject to random X-inactivation. OGT plays key roles in growth factor signalling, stem cell biology, epigenetics and possibly imprinting. The O-GlcNAcase, which removes O-GlcNAc, is subject to tight regulation by higher order chromatin structure. O-GlcNAc cycling plays an important role in the intrauterine environment wherein OGT expression is an important biomarker of placental stress. Regulation of O-GlcNAc cycling by X-inactivation, epigenetic regulation and nutrient-driven processes makes it an ideal candidate for a nutrient-dependent epigenetic regulator of human disease. In addition, O-GlcNAc cycling influences chromatin modifiers critical to the regulation and timing of normal development including the polycomb repression complex and the ten-eleven translocation proteins mediating DNA methyl cytosine demethylation. The pathway also impacts the hypothalamic-pituitary-adrenal axis critical to intrauterine programming influencing disease susceptibility in later life.
Stolzenberg, Danielle S; Grant, Patrick A; Bekiranov, Stefan
Hormones are essential regulators of many behaviors. Steroids bind either to nuclear or membrane receptors while peptides primarily act via membrane receptors. After a ligand binds, the conformational change in the receptor initiates changes in cell signaling cascades (membrane receptors) or direct alternations in DNA transcription (steroid receptors). Changes in gene transcription that result are responsible for protein production and ultimately behavioral modifications. A significant part of how hormones affect DNA transcription is via epigenetic modifications of DNA and/or the chromatin in which it is entwined. These alterations lead to transcriptional changes that ultimately define the phenotype and function of a given cell. Importantly we now know that environmental stimuli influence epigenetic marks, which in the context of neuroendocrinology can lead to behavioral changes. Importantly tracking epigenetic states and profiling the epigenome within cells require the use of epigenetic methodologies and subsequent data analysis. Here we describe the techniques of particular importance in the mapping of DNA methylation, histone modifications and occupancy of chromatin bound effector proteins that regulate gene expression. For researchers wanting to move into these levels of analysis we discuss the application of modern sequencing technologies applied in assays such as chromatin immunoprecipitation and the bioinformatics analysis involved in the rich datasets generated. Copyright © 2010 Elsevier Inc. All rights reserved.
Stolzenberg, Danielle; Grant, Patrick A.; Bekiranov, Stefan
Hormones are essential regulators of many behaviors. Steroids bind either to nuclear or membrane receptors while peptides primarily act via membrane receptors. After a ligand binds, the conformational change in the receptor initiates changes in cell signaling cascades (membrane receptors) or direct alternations in DNA transcription (steroid receptors). Changes in gene transcription that result are responsible for protein production and ultimately behavioral modifications. A significant part of how hormones affect DNA transcription is via epigenetic modifications of DNA and/or the chromatin in which it is entwined. These alterations lead to transcriptional changes that ultimately define the phenotype and function of a given cell. Importantly we now know that environmental stimuli influence epigenetic marks, which in the context of neuroendocrinology can lead to behavioral changes. Importantly tracking epigenetic states and profiling the epigenome within cells requires the use of epigenetic methodologies and subsequent data analysis. Here we describe the techniques of particular importance in the mapping of DNA methylation, histone modifications and occupancy of chromatin bound effector proteins that regulate gene expression. For researchers wanting to move into these levels of analysis we discuss the application of modern sequencing technologies applied in assays such as chromatin immunoprecipitation and the bioinformatics analysis involved in the rich datasets generated. PMID:20955712
Full Text Available BACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5 nasopharyngeal, 44% (8/18 esophageal, 76% (13/17 gastric, 50% (2/4 cervical, and 25% (3/12 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP in multiple primary tumors, including 93% (43/46 nasopharyngeal, 58% (25/43 esophageal, 88% (37/42 gastric and 63% (29/46 hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines. CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.
Full Text Available Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.
Sun, Hong; Shamy, Magdy; Costa, Max
Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.
Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L; Berkel, Tiffani D M; Pandey, Subhash C
Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, hold great therapeutic potential in the treatment and prevention of alcoholism. © 2014 Elsevier Inc. All rights reserved.
Kuasne, Hellen; Marchi, Fabio Albuquerque; Rogatto, Silvia Regina
in different cell types is acquired by chromatin modifications, which are established by epigenetic regulatory mechanisms involving DNA methylation, histone acetylation, and miRNAs. Recent evidence indicates that the dysregulation in these processes can result in the development of several diseases, including......Penile carcinoma (PeCa) represents an important public health problem in poor and developing countries. Despite its unpredictable behavior and aggressive treatment, there have only been a few reports regarding its molecular data, especially epigenetic mechanisms. The functional diversity...... cancer. Epigenetic alterations, such as the methylation of CpGs islands, may reveal candidates for the development of specific markers for cancer detection, diagnosis and prognosis. There are a few reports on the epigenetic alterations in PeCa, and most of these studies have only focused on alterations...
Krishnan, Harish R.; Sakharkar, Amul J.; Teppen, Tara L.; Berkel, Tiffani D.M.; Pandey, Subhash C.
Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure, but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, holds great therapeutic potential in the treatment and prevention of alcoholism. PMID:25131543
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...
Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DMA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin-regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.
Schwab, David; Bruinsma, Robijn
The role of chromatin structure in gene regulation has recently taken center stage in the field of epigenetics, phenomena that change the phenotype without changing the DNA sequence. Recent work has also shown that nucleosomes, a complex of DNA wrapped around a histone octamer, experience a sequence dependent energy landscape due to the variation in DNA bend stiffness with sequence composition. In this talk, we consider the role nucleosome positioning might play in the formation of heterochromatin, a compact form of DNA generically responsible for gene silencing. In particular, we discuss how different patterns of nucleosome positions, periodic or random, could either facilitate or suppress heterochromatin stability and formation.
Zhuo, Baowen; Yu, Juan; Chang, Luyuan; Lei, Jiafan; Wen, Zengqi; Liu, Cuifang; Mao, Guankun; Wang, Kehui; Shen, Jie; Xu, Xueqing
Genomic DNA of eukaryotic cells is hierarchically packaged into chromatin by histones. The dynamic organization of chromatin fibers plays a critical role in the regulation of gene transcription and other DNA-associated biological processes. Recently, numerous approaches have been developed to map the chromatin organization by characterizing chromatin accessibilities in genome-wide. However, reliable methods to quantitatively map chromatin accessibility are not well-established, especially not on a genome-wide scale. Here, we developed a modified MNase-seq for mouse embryonic fibroblasts, wherein chromatin was partially digested at multiple digestion times using micrococcal nuclease (MNase), allowing quantitative analysis of local yet genome-wide chromatin compaction. Our results provide strong evidence that the chromatin accessibility at promoter regions are positively correlated with gene activity. In conclusion, our assay is an ideal tool for the quantitative study of gene regulation in the perspective of chromatin accessibility. Copyright © 2017 Elsevier Inc. All rights reserved.
Mann, Jeffrey R
The field of epigenetics is expanding rapidly, yet there is persistent uncertainty in the definition of the term. The word was coined in the mid-twentieth century as a descriptor of how intrinsic, yet largely unknown, forces act with genes to channel progenitor cells along pathways of differentiation. Near the end of the twentieth century, epigenetics was defined more specifically as the study of changes in gene activity states. In some definitions, only those activity states that are inherited across cell division were considered. Other definitions were broader, also including activity states that are transient, or occurring in non-dividing cells. The greatest point of disagreement in these current definitions, is if the term should concern only inherited activity states. To alleviate this disparity, an alternative term, 'memigenetics', could be used in place of epigenetics to describe inherited chromatin activity states. The advantage of this term is that it is self-defining, and would serve to emphasize the important concept of cell memory. It would also free the term epigenetics to be used in a broader sense in accord with the meaning of the prefix 'epi', that is, as a descriptor of what is 'over' DNA at any point in time.
Minocherhomji, Sheroy; Madon, Prochi F; Parikh, Firuza R
Infertility is a complex human condition and is known to be caused by numerous factors including genetic alterations and abnormalities. Increasing evidence from studies has associated perturbed epigenetic mechanisms with spermatogenesis and infertility. However, there has been no consensus...... with higher order organisation of chromatin in genes associated with infertility and pericentromeric regions of chromosomes, particularly 9 and Y, could further identify causes of idiopathic infertility. Determining the association between DNA methylation, chromatin state, and noncoding RNAs...
Ahmad, Ayaz; Zhang, Yong; Cao, Xiao-Feng
Epigenetics refers to the study of heritable changes in gene expression or cellular phenotype without changes in DNA sequence. Epigenetic regulation of gene expression is accomplished by DNA methylation, histone modifications, histone variants, chromatin remodeling, and may involve small RNAs. DNA methylation at cytosine is carried out by enzymes called DNA Methyltransferases and is involved in many cellular processes, such as silencing of transposable elements and pericentromeric repeats, X-...
Völker-Albert, Moritz Carl; Pusch, Miriam Caroline; Fedisch, Andreas; Schilcher, Pierre; Schmidt, Andreas; Imhof, Axel
The structure of chromatin is critical for many aspects of cellular physiology and is considered to be the primary medium to store epigenetic information. It is defined by the histone molecules that constitute the nucleosome, the positioning of the nucleosomes along the DNA and the non-histone proteins that associate with it. These factors help to establish and maintain a largely DNA sequence-independent but surprisingly stable structure. Chromatin is extensively disassembled and reassembled during DNA replication, repair, recombination or transcription in order to allow the necessary factors to gain access to their substrate. Despite such constant interference with chromatin structure, the epigenetic information is generally well maintained. Surprisingly, the mechanisms that coordinate chromatin assembly and ensure proper assembly are not particularly well understood. Here, we use label free quantitative mass spectrometry to describe the kinetics of in vitro assembled chromatin supported by an embryo extract prepared from preblastoderm Drosophila melanogaster embryos. The use of a data independent acquisition method for proteome wide quantitation allows a time resolved comparison of in vitro chromatin assembly. A comparison of our in vitro data with proteomic studies of replicative chromatin assembly in vivo reveals an extensive overlap showing that the in vitro system can be used for investigating the kinetics of chromatin assembly in a proteome-wide manner. PMID:26811354
Carlos A. Aguilar
Full Text Available Following injury, adult skeletal muscle undergoes a well-coordinated sequence of molecular and physiological events to promote repair and regeneration. However, a thorough understanding of the in vivo epigenomic and transcriptional mechanisms that control these reparative events is lacking. To address this, we monitored the in vivo dynamics of three histone modifications and coding and noncoding RNA expression throughout the regenerative process in a mouse model of traumatic muscle injury. We first illustrate how both coding and noncoding RNAs in tissues and sorted satellite cells are modified and regulated during various stages after trauma. Next, we use chromatin immunoprecipitation followed by sequencing to evaluate the chromatin state of cis-regulatory elements (promoters and enhancers and view how these elements evolve and influence various muscle repair and regeneration transcriptional programs. These results provide a comprehensive view of the central factors that regulate muscle regeneration and underscore the multiple levels through which both transcriptional and epigenetic patterns are regulated to enact appropriate repair and regeneration.
Full Text Available Bridget M Nugent,1 Margaret M McCarthy2 1Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA Abstract: The developing brain is subject to modifying influences, both in utero and early postnatally. Some of these are intrinsic, such as gonadal steroids, while others are externally imposed, such as maternal nutrition or stress. All of these variables can have enduring consequences by imposing epigenetic modifications on the genome that alter set points for activation in adulthood, thereby reflecting early-life programming. In this review, we provide an overview of the most well studied epigenetic processes that occur in the brain. Next, we summarize the studies to date that have implicated gonadal steroids, stress exposure, and nutritional deficits/excess in changes in neural epigenetic marks, which ultimately alter brain development, but we also note that this field is still in its infancy. Epigenetic regulators include DNA methylation, changes to the chromatin via acetylation and other chemical modifiers, and noncoding RNAs all of which impact the expression of specific genes. In this way gonadal steroids in the developing male fetus direct masculinization of adult brain and behavior, and similarly in utero exposure to a high-fat or calorie-restricted diet impacts glucose metabolism and body fat composition throughout life. Stress early in life changes the sensitivity of the hypothalamic–pituitary–adrenal (HPA axis to subsequent stressors and this too is mediated, at least in part, by epigenetic changes to key genes to alter the responsiveness threshold. Epigenetics is the integration of the environment and the genome, and hormones and nutrition provide the bridge that allows that integration to occur. Keywords: epigenetics, early-life programming, brain development, hormones, nutrition
Georgel, Philippe T
Within the past two decades, the fields of chromatin structure and function and transcription regulation research started to fuse and overlap, as evidence mounted to support a very strong regulatory role in gene expression that was associated with histone post-translational modifications, DNA methylation, as well as various chromatin-associated proteins (the pillars of the "Epigenetics" building). The fusion and convergence of these complementary fields is now often simply referred to as "Epigenetics". During these same 20 years, numerous new research groups have started to recognize the importance of chromatin composition, conformation, and its plasticity. However, as the field started to grow exponentially, its growth came with the spreading of several important misconceptions, which have unfortunately led to improper or hasty conclusions. The goal of this short "opinion" piece is to attempt to minimize future misinterpretations of experimental results and ensure that the right sets of experiment are used to reach the proper conclusion, at least as far as epigenetic mechanisms are concerned.
Phillips-Cremins, Jennifer E.; Corces, Victor G.
A growing body of evidence suggests that insulators have a primary role in orchestrating the topological arrangement of higher-order chromatin architecture. Insulator-mediated long-range interactions can influence the epigenetic status of the genome and, in certain contexts, may have important effects on gene expression. Here we discuss higher-order chromatin organization as a unifying mechanism for diverse insulator actions across the genome. PMID:23706817
Dupéré-Richer, Daphné; Licht, Jonathan D
Next generation sequencing and large-scale analysis of patient specimens has created a more complete picture of multiple myeloma (MM) revealing that epigenetic deregulation is a prominent factor in MM pathogenesis. Over half of MM patients have mutations in genes encoding epigenetic modifier enzymes. The DNA methylation profile of MM is related to the stage of the disease and certain classes of mutations in epigenetic modifiers are more prevalent upon disease relapse, suggesting a role in disease progression. Many small molecules targeting regulators of epigenetic machinery have been developed and clinical trials are underway for some of these in MM. Recent findings suggest that epigenetic targeting drugs could be an important strategy to cure MM. Combining these agents along with other strategies to affect the MM cell such as immunomodulatory drugs and proteasome inhibitors may enhance efficacy of combination regimens in MM.
Spiegel, Amy M.; Sewal, Angila S.; Rapp, Peter R.
Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review…
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.
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
Mammary gland development and differentiation occur mostly postnatally. Chromatin organization plays a key role in transcriptional and epigenetic regulation during development and differentiation. Considerable knowledge of the systemic hormones and local growth factors important for development and ...
Full Text Available Epigenetic research has been focused on cell-type-specific regulation; less is known about common features of epigenetic programming shared by diverse cell types within an organism. Here, we report a modified method for chromatin immunoprecipitation and deep sequencing (ChIP-Seq and its use to construct a high-resolution map of the Drosophila melanogaster key histone marks, heterochromatin protein 1a (HP1a and RNA polymerase II (polII. These factors are mapped at 50-bp resolution genome-wide and at 5-bp resolution for regulatory sequences of genes, which reveals fundamental features of chromatin modification landscape shared by major adult Drosophila cell types: the enrichment of both heterochromatic and euchromatic marks in transposons and repetitive sequences, the accumulation of HP1a at transcription start sites with stalled polII, the signatures of histone code and polII level/position around the transcriptional start sites that predict both the mRNA level and functionality of genes, and the enrichment of elongating polII within exons at splicing junctions. These features, likely conserved among diverse epigenomes, reveal general strategies for chromatin modifications.
Taby, Rodolphe; Issa, Jean-Pierre J
Epigenetics refers to stable alterations in gene expression with no underlying modifications in the genetic sequence and is best exemplified by differentiation, in which multiple cell types diverge...
Perfus-Barbeoch, Laetitia; Castagnone-Sereno, Philippe; Reichelt, Michael; Fneich, Sara; Roquis, David; Pratx, Loris; Cosseau, Céline; Grunau, Christoph; Abad, Pierre
Root-knot nematodes of the genus Meloidogyne are biotrophic plant parasites that exhibit different life cycles and reproduction modes, ranging from classical amphimixis to obligatory mitotic parthenogenesis (apomixis), depending on the species. Meloidogyne incognita, an apomictic species, exhibits a worldwide distribution and a wide host range affecting more than 3000 plant species. Furthermore, evidences suggest that apomixis does not prevent M. incognita from adapting to its environment in contrast to what is expected from mitotic parthenogenesis that should theoretically produce clonal progenies. This raises questions about mechanisms of genome plasticity leading to genetic variation and adaptive evolution in apomictic animals. We reasoned that epigenetic mechanisms might in part be responsible for the generation of phenotypic variants that provide potential for rapid adaptation. We established therefore a pipeline to investigate the principal carriers of epigenetic information, DNA methylation and post-translational histone modifications. Even if M. incognita possesses the epigenetic machinery i.e., chromatin modifying enzymes, 5-methyl-cytosine and 5-hydroxy-methyl-cytosine content is absent or very weak. In contrast, we demonstrated that the canonical histone modifications are present and chromatin shows typical nucleosome structure. This work is the first characterization of carriers of epigenetic information in M. incognita and constitutes a preamble to further investigate if M. incognita development and its adaptation to plant hosts are under epigenetic control. Our pipeline should allow performing similar types of studies in any non-model organism.
Full Text Available Root-knot nematodes of the genus Meloidogyne are biotrophic plant parasites that exhibit different reproduction modes, ranging from classical amphimixis to obligatory mitotic parthenogenesis (apomixis, depending on the species. Meloidogyne incognita, an apomictic species, exhibits a worldwide distribution and a wide host range affecting more than 3,000 plant species. Furthermore, evidences suggest that apomixis does not prevent M. incognita from adapting to its environment in contrast to what is expected from mitotic parthenogenesis that should theoretically produce clonal progenies. This raises questions about mechanisms of genome plasticity leading to genetic variation and adaptive evolution in apomictic animals. We reasoned that epigenetic mechanisms might in part be responsible for the generation of phenotypic variants that provide potential for rapid adaptation. We investigated therefore the principal carriers of epigenetic information, DNA methylation and post-translational histone modifications. Even if M. incognita possesses the epigenetic machinery i.e. chromatin modifying enzymes, 5-methyl-cytosine and 5-hydroxy-methyl-cytosine content is absent or very weak. In contrast, we demonstrated that the canonical histone modifications are present and chromatin shows typical nucleosome structure. This work is the first characterization of carriers of epigenetic information in M. incognita and constitutes a preamble to further investigate whether M. incognita development and its adaptation to plant hosts are under epigenetic control.
With the goal of discussing how epigenetic control and chromatin remodeling contribute to the various processes that lead to cellular plasticity and disease, this symposium marks the collaboration between the Institut National de la Santé et de la Recherche Médicale (INSERM) in France and the University of California, Irvine (UCI). Organized by Paolo Sassone-Corsi (UCI) and held at the Beckman Center of the National Academy of Sciences at the UCI campus December 15–16, 2011, this was the first of a series of international conferences on epigenetics dedicated to the scientific community in Southern California. The meeting also served as the official kick off for the newly formed Center for Epigenetics and Metabolism at the School of Medicine, UCI (http://cem.igb.uci.edu). PMID:22414797
Federman, Noel; Zalcman, Gisela; de la Fuente, Verónica; Fustiñana, Maria Sol; Romano, Arturo
Memory consolidation requires de novo mRNA and protein synthesis. Transcriptional activation is controlled by transcription factors, their cofactors and repressors. Cofactors and repressors regulate gene expression by interacting with basal transcription machinery, remodeling chromatin structure and/or chemically modifying histones. Acetylation is the most studied epigenetic mechanism of histones modifications related to gene expression. This process is regulated by histone acetylases (HATs) and histone deacetylases (HDACs). More than 5 years ago, we began a line of research about the role of histone acetylation during memory consolidation. Here we review our work, presenting evidence about the critical role of this epigenetic mechanism during consolidation of context-signal memory in the crab Neohelice granulata, as well as during consolidation of novel object recognition memory in the mouse Mus musculus. Our evidence demonstrates that histone acetylation is a key mechanism in memory consolidation, functioning as a distinctive molecular feature of strong memories. Furthermore, we found that the strength of a memory can be characterized by its persistence or its resistance to extinction. Besides, we found that the role of this epigenetic mechanism regulating gene expression only in the formation of strongest memories is evolutionarily conserved. Copyright © 2014 Elsevier Ltd. All rights reserved.
Palma, K.; Thorgrimsen, S.; Malinovsky, F.G.
Certain pathogens deliver effectors into plant cells to modify host protein targets and thereby suppress immunity. These target modifications can be detected by intracellular immune receptors, or Resistance (R) proteins, that trigger strong immune responses including localized host cell death....... In a screen for lazarus (laz) mutants that suppress acd11 death we identified two genes, LAZ2 and LAZ5. LAZ2 encodes the histone lysine methyltransferase SDG8, previously shown to epigenetically regulate flowering time via modification of histone 3 (H3). LAZ5 encodes an RPS4-like R-protein, defined by several...... dominant negative alleles. Microarray and chromatin immunoprecipitation analyses showed that LAZ2/SDG8 is required for LAZ5 expression and H3 lysine 36 trimethylation at LAZ5 chromatin to maintain a transcriptionally active state. We hypothesize that LAZ5 triggers cell death in the absence of ACD11...
Toro, Carlos A; Wright, Hollis; Aylwin, Carlos F; Ojeda, Sergio R; Lomniczi, Alejandro
Polycomb group (PcG) proteins control the timing of puberty by repressing the Kiss1 gene in hypothalamic arcuate nucleus (ARC) neurons. Here we identify two members of the Trithorax group (TrxG) of modifiers, mixed-lineage leukemia 1 (MLL1), and 3 (MLL3), as central components of an activating epigenetic machinery that dynamically counteracts PcG repression. Preceding puberty, MLL1 changes the chromatin configuration at the promoters of Kiss1 and Tac3, two genes required for puberty to occur, from repressive to permissive. Concomitantly, MLL3 institutes a chromatin structure that changes the functional status of a Kiss1 enhancer from poised to active. RNAi-mediated, ARC-specific Mll1 knockdown reduced Kiss1 and Tac3 expression, whereas CRISPR-Cas9-directed epigenome silencing of the Kiss1 enhancer selectively reduced Kiss1 activity. Both interventions delay puberty and disrupt reproductive cyclicity. Our results demonstrate that an epigenetic switch from transcriptional repression to activation is crucial to the regulatory mechanism controlling the timing of mammalian puberty.
Bahabri, Rihab R.
Activities of DNA are to a great extent controlled epigenetically through the internal struc- ture of chromatin. This structure is dynamic and is influenced by different modifications of histone proteins. Various combinations of epigenetic modification of histones pinpoint to different functional regions of the DNA determining the so-called chromatin states. How- ever, the characterization of chromatin states by the DNA sequence properties remains largely unknown. In this study we aim to explore whether DNA sequence patterns in the human genome can characterize different chromatin states. Using DNA sequence motifs we built binary classifiers for each chromatic state to eval- uate whether a given genomic sequence is a good candidate for belonging to a particular chromatin state. Of four classification algorithms (C4.5, Naive Bayes, Random Forest, and SVM) used for this purpose, the decision tree based classifiers (C4.5 and Random Forest) yielded best results among those we evaluated. Our results suggest that in general these models lack sufficient predictive power, although for four chromatin states (insulators, het- erochromatin, and two types of copy number variation) we found that presence of certain motifs in DNA sequences does imply an increased probability that such a sequence is one of these chromatin states.
This chapter is intended to provide a timely overview of the current state of research at the intersection of nutrition and epigenetics. I begin by describing epigenetics and molecular mechanisms of eigenetic regulation, then highlight four classes of nutritional exposures currently being investiga...
Studies have demonstrated that epigenetic changes such as DNA methylation, histone modification, and chromatin remodeling are linked to an increased inflammatory response as well as increased risk for chronic disease development. A few studies have begun to investigate whether dietary nutrients play...
Fujimoto, Ryo; Sasaki, Taku; Ishikawa, Ryo; Osabe, Kenji; Kawanabe, Takahiro; Dennis, Elizabeth S
Natural variation is defined as the phenotypic variation caused by spontaneous mutations. In general, mutations are associated with changes of nucleotide sequence, and many mutations in genes that can cause changes in plant development have been identified. Epigenetic change, which does not involve alteration to the nucleotide sequence, can also cause changes in gene activity by changing the structure of chromatin through DNA methylation or histone modifications. Now there is evidence based on induced or spontaneous mutants that epigenetic changes can cause altering plant phenotypes. Epigenetic changes have occurred frequently in plants, and some are heritable or metastable causing variation in epigenetic status within or between species. Therefore, heritable epigenetic variation as well as genetic variation has the potential to drive natural variation.
Smith, Cassandra L
The GTC Cancer Summit: Novel Approaches to Drug Discovery was divided into two parallel tracks: the 2nd Cancer Epigenetics Conference, and the Protein Kinases and Drug Design Conference. The 2nd Cancer Epigenetics Conference focused on exciting changes in drug discovery that include an unprecedented private and public collaboration on drug discovery in epigenetics through the Structural Genomics Consortium (SGC), which has led to several major breakthroughs including: the development of small-molecule inhibitors that interfere with protein interactions, especially bromodomain-containing protein acetylation readers; the indirect but successful targeting of the elusive MYC oncogene; and the identification of epigenetic drugs that are disease-specific. Also reported were the development of clinically useful DNA methylation assays; cell, peptide and protein arrays for testing antibody- and protein-binding specificity; and tools for chromatin capture and DNA modification analysis. Several groups reported on the lack of specificity of some commercial, but unnamed, antibodies used for epigenetic studies.
Wolffe, Alan P
The Third Edition of Chromatin: Structure and Function brings the reader up-to-date with the remarkable progress in chromatin research over the past three years. It has been extensively rewritten to cover new material on chromatin remodeling, histone modification, nuclear compartmentalization, DNA methylation, and transcriptional co-activators and co-repressors. The book is written in a clear and concise fashion, with 60 new illustrations. Chromatin: Structure and Function provides the reader with a concise and coherent account of the nature, structure, and assembly of chromatin and its active
Acevedo, Nathalie; Reinius, Lovisa E; Vitezic, Morana
BACKGROUND: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate...... factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when...
Alegría-Torres, Jorge Alejandro; Baccarelli, Andrea; Bollati, Valentina
The concept of “lifestyle” includes different factors such as nutrition, behavior, stress, physical activity, working habits, smoking and alcohol consumption. Increasing evidence shows that environmental and lifestyle factors may influence epigenetic mechanisms, such as DNA methylation, histone acetylation and microRNA expression. Several lifestyle factors have been identified that might modify epigenetic patterns, such as diet, obesity, physical activity, tobacco smoking, alcohol consumption, environmental pollutants, psychological stress, and working on night shifts. Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied lifestyle factors in relation to histone modifications and miRNAs. Here, we review current evidence indicating that lifestyle factors might affect human health via epigenetic mechanisms. PMID:22122337
Forzani, C; Loulergue, C; Lobréaux, S; Briat, J F; Lebrun, M
Expression of a maize cDNA encoding a high mobility group (HMG) I/Y protein enables growth of transformed yeast on a medium containing toxic nickel concentrations. No difference in the nickel content was measured between yeast cells expressing either the empty vector or the ZmHMG I/Y2 cDNA. The ZmHMG I/Y2 protein contains four AT hook motifs known to be involved in binding to the minor groove of AT-rich DNA regions. HMG I/Y proteins may act as architectural elements modifying chromatin structure. Indeed, a ZmHMG I/Y2-green fluorescent protein fusion protein was observed in yeast nuclei. Nickel toxicity has been suggested to occur through an epigenetic mechanism related to chromatin condensation and DNA methylation, leading to the silencing of neighboring genes. Therefore, the ZmHMG I/Y2 protein could prevent nickel toxicity by interfering with chromatin structure. Yeast cell growth in the presence of nickel and yeast cells expressing the ZmHMG I/Y2 cDNA increased telomeric URA3 gene silencing. Furthermore, ZmHMG I/Y2 restored a wild-type level of nickel sensitivity to the yeast (Delta)rpd3 mutant. Therefore, nickel resistance of yeast cells expressing the ZmHMG I/Y2 cDNA is likely achieved by chromatin structure modification, restricting nickel accessibility to DNA.
Sutherland, Jessica E; Costa, Max
DNA methylation and histone modification promote changes in chromatin structure that may affect gene expression in a heritable manner without directly altering the genome. As such, these phenomena are considered to be epigenetic in nature and are believed to contribute to the normal processes of human development but also to aberrant disease states such as cancer. Epigenetic processes probably contribute mechanistically to toxicant-induced changes in gene expression and cancer. Nickel is a potent human carcinogen that has been shown to alter DNA methylation patterns and affect histone acetylation status. Both of these changes are associated with the proximity of the affected regions to heterochromatin. The two processes probably occur in concert in mammalian cells. However, in yeast cells, DNA methylation is absent, and nickel is capable of regulating gene expression through changes in acetylation of the lysine residues in the N terminal tail of histone H4. Arsenic is another important environmental carcinogen, and it is methylated during its metabolism. Hence, it has been proposed that arsenic metabolism may deplete intracellular methyl group stores and thereby lead to changes in DNA methylation that may be involved in carcinogenesis. However, the data concerning DNA methylation changes following arsenic exposure are equivocal, leading researchers to propose that DNA hypo- and hypermethylation are both important in the development of arsenic-induced cancers. Heightened awareness by toxicologists of the importance of epigenetics in normal human development and in carcinogenesis should lead to the identification of other toxicants that manifest their effects, at least in part, via epigenetic mechanisms.
Burgess, Rebecca C; Misteli, Tom; Oberdoerffer, Philipp
Aging brings about numerous cellular defects. Amongst the most prominent are elevated levels of persistent DNA damage, changes to chromatin structure and epigenetic modifications, and alterations of global transcription programs. These are not independent events and recent work begins to shed light on the intricate interplay between these aging-related defects. Published by Elsevier Ltd.
Lester, Barry M.; Tronick, Edward; Nestler, Eric; Abel, Ted; Kosofsky, Barry; Kuzawa, Christopher W.; Marsit, Carmen J.; Maze, Ian; Meaney, Michael J.; Monteggia, Lisa M.; Reul, Johannes M. H. M.; Skuse, David H.; Sweatt, J. David; Wood, Marcelo A.
Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level. PMID:21615751
Biliński, Przemysław; Wojtyła, Andrzej; Kapka-Skrzypczak, Lucyna; Chwedorowicz, Roman; Cyranka, Małgorzata; Studziński, Tadeusz
The interaction between environmental signals and genes has now taken on a clear molecular form as demonstrated by stable changes in chromatin structure. These changes occur through activation or repression of specific gene programmes by a combination of chromatin remodelling, activation and enzymatic modification of DNA and histones as well as nucleosomal subunit exchange. Recent research investigating the molecular mechanisms controlling drug-induced transcriptional, behavioural and synaptic activity has shown a direct role for chromatin remodelling--termed as epigenetic regulation--of neuronal gene programmes and subsequent addictive behaviour arising from it. Recent data suggest that repeated exposure to certain drugs promotes changes in levels of histone acetylation, phosphorylation and methylation, together with alterations in DNA methylation levels in the neurons of the brain reward centre, localised in the Nucleus Accumbens (NAc) region of the limbic system. The combination of acetylating, phosphorylating and methylating H3 and H4 histone tails alter chromatin compaction thereby promoting altered levels of cellular gene expression. Histone modifications, which weaken histone interaction with DNA or that promote recruitment of transcriptional activating complexes, correlate with permissive gene expression. Histone deacetylation, (which strengthen histone: DNA contacts), or histone methylation, (which recruits repressive complexes to chromatin), promote a state of transcriptional repression. Using animal models, acute cocaine treatment increases H4 acetylation at acutely regulated gene promoters, whereas H3 acetylation appears to predominate at chronically induced promoters. Chronic cocaine and alcohol treatment activate and repress many genes such as FosB, Cdk5, and Bdnf, where their dysregulation, at the chromatin level, contribute to the development and maintenance of addiction. Following drug exposure, it is still unknown, howver, how long these changes
de las Heras, Jose I.; Saiz-Ros, Natalia; Makarov, Alexandr A.; Lazou, Vassiliki; Meinke, Peter; Waterfall, Martin; Kelly, David A.; Schirmer, Eric C.
Changes in the peripheral distribution and amount of condensed chromatin are observed in a number of diseases linked to mutations in the lamin A protein of the nuclear envelope. We postulated that lamin A interactions with nuclear envelope transmembrane proteins (NETs) that affect chromatin structure might be altered in these diseases and so screened thirty-one NETs for those that promote chromatin compaction as determined by an increase in the number of chromatin clusters of high pixel intensity. One of these, NET23 (also called STING, MITA, MPYS, ERIS, Tmem173), strongly promoted chromatin compaction. A correlation between chromatin compaction and endogenous levels of NET23/STING was observed for a number of human cell lines, suggesting that NET23/STING may contribute generally to chromatin condensation. NET23/STING has separately been found to be involved in innate immune response signaling. Upon infection cells make a choice to either apoptose or to alter chromatin architecture to support focused expression of interferon genes and other response factors. We postulate that the chromatin compaction induced by NET23/STING may contribute to this choice because the cells expressing NET23/STING eventually apoptose, but the chromatin compaction effect is separate from this as the condensation was still observed when cells were treated with Z-VAD to block apoptosis. NET23/STING-induced compacted chromatin revealed changes in epigenetic marks including changes in histone methylation and acetylation. This indicates a previously uncharacterized nuclear role for NET23/STING potentially in both innate immune signaling and general chromatin architecture. PMID:25386906
Veazey, Kylee J; Carnahan, Mindy N; Muller, Daria; Miranda, Rajesh C; Golding, Michael C
From studies using a diverse range of model organisms, we now acknowledge that epigenetic changes to chromatin structure provide a plausible link between environmental teratogens and alterations in gene expression leading to disease. Observations from a number of independent laboratories indicate that ethanol (EtOH) has the capacity to act as a powerful epigenetic disruptor and potentially derail the coordinated processes of cellular differentiation. In this study, we sought to examine whether primary neurospheres cultured under conditions maintaining stemness were susceptible to alcohol-induced alterations in the histone code. We focused our studies on trimethylated histone 3 lysine 4 and trimethylated histone 3 lysine 27, as these are 2 of the most prominent posttranslational histone modifications regulating stem cell maintenance and neural differentiation. Primary neurosphere cultures were maintained under conditions promoting the stem cell state and treated with EtOH for 5 days. Control and EtOH-treated cellular extracts were examined using a combination of quantitative RT-PCR and chromatin immunoprecipitation techniques. We find that the regulatory regions of genes controlling both neural precursor cell identity and processes of differentiation exhibited significant declines in the enrichment of the chromatin marks examined. Despite these widespread changes in chromatin structure, only a small subset of genes including Dlx2, Fabp7, Nestin, Olig2, and Pax6 displayed EtOH-induced alterations in transcription. Unexpectedly, the majority of chromatin-modifying enzymes examined including members of the Polycomb Repressive Complex displayed minimal changes in expression and localization. Only transcripts encoding Dnmt1, Uhrf1, Ehmt1, Ash2 l, Wdr5, and Kdm1b exhibited significant differences. Our results indicate that primary neurospheres maintained as stem cells in vitro are susceptible to alcohol-induced perturbation of the histone code and errors in the epigenetic
An Insight into the Secondary Metabolism of Muscodor yucatanensis: Small-Molecule Epigenetic Modifiers Induce Expression of Secondary Metabolism-Related Genes and Production of New Metabolites in the Endophyte.
Qadri, Masroor; Nalli, Yedukondalu; Jain, Shreyans K; Chaubey, Asha; Ali, Asif; Strobel, Gary A; Vishwakarma, Ram A; Riyaz-Ul-Hassan, Syed
Muscodor spp. are proficient producers of bioactive volatile organic compounds (VOCs) with many potential applications. However, all members of this genus produce varying amounts and types of VOCs which suggests the involvement of epigenetics as a possible explanation. The members of this genus are poorly explored for the production of soluble compounds (extrolites). In this study, the polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) genes from an endophyte, Muscodor yucatanensis Ni30, were cloned and sequenced. The PKS genes belonged to reduced, partially reduced, non-reduced, and highly reduced subtypes. Strains over-expressing PKS genes were developed through the use of small-molecule epigenetic modifiers (suberoylanilide hydroxamic acid (SAHA) and 5-azacytidine). The putative epigenetic variants of this organism differed considerably from the wild type in morphological features and cultural characteristics as well as metabolites that were produced. Each variant produced a different set of VOCs distinct from the wild type, and several VOCs including methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)hexane-2,4-diol and 2-carboxymethyl-3-n-hexylmaleic appeared in the variant strains, the production of which could be attributed to the activity of otherwise silent PKS genes. The bioactive extrolite brefeldin A was isolated and characterized from the wild type. However, this metabolite was not detected in EV-1, but instead, two other products were isolated and characterized as ergosterol and xylaguaianol C. Hence, M. yucatanensis has the genetic potential to produce several previously undetectable VOCs and organic solvent soluble products. It is also the case that small-molecule epigenetic modifiers can be used to produce stable variant strains of fungi with the potential to produce new molecules. Finally, this work hints to the prospect that the epigenetics of an endophytic microorganism can be influenced by any number of environmental and chemical
Simon, Stacey A; Meyers, Blake C
Epigenetic modifications in plants can be directed and mediated by small RNAs (sRNAs). This regulation is composed of a highly interactive network of sRNA-directed DNA methylation, histone, and chromatin modifications, all of which control transcription. Identification and functional characterization of components of the siRNA-directed DNA methylation pathway have provided insights into epigenetic pathways that form heterochromatin and into chromatin-based pathways for gene silencing, paramutation, genetic imprinting, and epigenetic reprogramming. Next-generation sequencing technologies have facilitated new discoveries and have helped create a basic blueprint of the plant epigenome. As the multiple layers of epigenetic regulation in plants are dissected, a more comprehensive understanding of the biological importance of epigenetic marks and states has been developed. Copyright © 2010 Elsevier Ltd. All rights reserved.
Feinberg, Andrew P.
The aim of this review is to summarize an evolution of thinking about the epigenetic basis of human cancer, from the earliest studies of altered DNA methylation in cancer to the modern comprehensive epigenomic era. Converging data from epigenetic studies of primary cancers and from experimental studies of chromatin in development and epithelial–mesenchymal transition suggest a role for epigenetic stochasticity as a driving force of cancer, with Darwinian selection of tumour cells at the expense of the host. This increased epigenetic stochasticity appears to be mediated by large-scale changes in DNA methylation and chromatin in domains associated with the nuclear lamina. The implications for diagnosis include the potential to identify stochastically disrupted progenitor cells years before cancer develops, and to target drugs to epigenetic drivers of gene expression instability rather than to mean effects per se. PMID:24635672
Angarica, Vladimir Espinosa; Del Sol, Antonio
Epigenetics play a central role in the regulation of many important cellular processes, and dysregulations at the epigenetic level could be the source of serious pathologies, such as neurological disorders affecting brain development, neurodegeneration, and intellectual disability. Despite significant technological advances for epigenetic profiling, there is still a need for a systematic understanding of how epigenetics shapes cellular circuitry, and disease pathogenesis. The development of accurate computational approaches for analyzing complex epigenetic profiles is essential for disentangling the mechanisms underlying cellular development, and the intricate interaction networks determining and sensing chromatin modifications and DNA methylation to control gene expression. In this chapter, we review the recent advances in the field of "computational epigenetics," including computational methods for processing different types of epigenetic data, prediction of chromatin states, and study of protein dynamics. We also discuss how "computational epigenetics" has complemented the fast growth in the generation of epigenetic data for uncovering the main differences and similarities at the epigenetic level between individuals and the mechanisms underlying disease onset and progression.
Turner, Anne-Marie W; Margolis, David M
The formation of a latent reservoir of Human Immunodeficiency Virus (HIV) infection hidden from immune clearance remains a significant obstacle to approaches to eradicate HIV infection. Towards an understanding of the mechanisms of HIV persistence, there is a growing body of work implicating epigenetic regulation of chromatin in establishment and maintenance of this latent reservoir. Here we discuss recent advances in the field of chromatin regulation, specifically in our understanding of the histone code, and how these discoveries relate to our current knowledge of the chromatin mechanisms linked to HIV transcriptional repression and the reversal of latency. We also examine mechanisms unexplored in the context of HIV latency and briefly discuss current therapies aimed at the induction of proviral expression within latently infected cells. We aim to emphasize that a greater understanding of the epigenetic mechanisms which govern HIV latency could lead to new therapeutic targets for latency reversal and clearance cure strategies.
Festuccia, Nicola; Gonzalez, Inma; Navarro, Pablo
The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key property of authentic epigenetic regulation is being independent from the instructive signals used for its establishment. This makes epigenetic regulation, particularly epigenetic silencing, extremely robust and powerful to lock regulatory states and stabilise cell identity. In line with this, the establishment of epigenetic silencing during development restricts cell potency and maintains the cell fate choices made by transcription factors (TFs). However, how more immature cells that have not yet established their definitive fate maintain their transitory identity without compromising their responsiveness to signalling cues remains unclear. A paradigmatic example is provided by pluripotent embryonic stem (ES) cells derived from a transient population of cells of the blastocyst. Here, we argue that ES cells represent an interesting "epigenetic paradox": even though they are captured in a self-renewing state characterised by extremely efficient maintenance of their identity, which is a typical manifestation of robust epigenetic regulation, they seem not to heavily rely on classical epigenetic mechanisms. Indeed, self-renewal strictly depends on the TFs that previously instructed their undifferentiated identity and relies on a particular signalling-dependent chromatin state where repressive chromatin marks play minor roles. Although this "epigenetic paradox" may underlie their exquisite responsiveness to developmental cues, it suggests that alternative mechanisms to faithfully propagate gene regulatory states might be prevalent in ES cells. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Vatolin, Sergei; Khan, Shahper N.; Reu, Frederic J.
Current methods to study chromatin configuration are not well suited for high throughput drug screening since they require large cell numbers and multiple experimental steps that include centrifugation for isolation of nuclei or DNA. Here we show that site specific chromatin analysis can be achieved in one step by simply performing direct chromatin PCR (DC-PCR) on cells. The basic underlying observation was that standard hypotonic PCR buffers prevent global cellular chromatin solubilization during thermal cycling while more loosely organized chromatin can be amplified. Despite repeated heating to >90°C, 41 of 61 tested 5′ sequences of silenced genes (CDKN2A, PU.1, IRF4, FOSB, CD34) were not amplifiable while 47 could be amplified from expressing cells. Two gene regions (IRF4, FOSB) even required pre-heating of cells in isotonic media to allow this differentiation; otherwise none of 19 assayed sequences yielded PCR products. Cells with baseline expression or epigenetic reactivation gave similar DC-PCR results. Silencing during differentiation of CD34 positive cord blood cells closed respective chromatin while treatment of myeloma cells with an IRF4 transcriptional inhibitor opened a site to DC-PCR that was occupied by RNA polymerase II and NFκB as determined by ChIP. Translation into real-time PCR can not be achieved with commercial real-time PCR buffers which potently open chromatin, but even with simple ethidium bromide addition to standard PCR mastermix we were able to identify hits in small molecules screens that suppressed IRF4 expression or reactivated CDKN2A in myeloma cells using densitometry or visual inspection of PCR plates under UV light. While need in drug development inspired this work, application to genome-wide analysis appears feasible using phi29 for selective amplification of open cellular chromatin followed by library construction from supernatants since such supernatants yielded similar results as gene specific DC-PCR. PMID:22984542
Abbas, Ata; Hall, J Adam; Patterson, William L; Ho, Emily; Hsu, Anna; Al-Mulla, Fahd; Georgel, Philippe T
Epidemiologic studies have revealed that diets rich in sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in prostate cancer incidence. The chemo-preventive role of SFN is associated with its histone de-acetylase inhibitor activity. However, the effect of SFN on chromatin composition and dynamic folding, especially in relation to HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 2 prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in chromatin structure and composition. The SFN-mediated changes in levels of histone post-translational modifications, more specifically acetylation of histone H3 lysine 18 and di-methylation of histone H3 lysine 4, 2 modifications linked with high risk of prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region. Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known chromatin compactor, were altered in SFN treated prostate cancer cells. Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in prostate cancer cells. This ability of SFN to modify chromatin composition and structure associated with target gene expression provides a new model by which dietary phytochemicals may exert their chemoprevention activity.
Recent progress has been made in the understanding of the physical properties of chromatin -- the dense complex of DNA and histone proteins that occupies the nuclei of plant and animal cells. Here I will focus on the two lowest levels of the hierarchy of DNA folding into the chromatin complex: (i) the nucleosome, the chromatin repeating unit consisting of a globular aggregate of eight histone proteins with the DNA wrapped around: its overcharging, the DNA unwrapping transition, the ''sliding'...
Epigenetics refers to the study of heritable changes in genome function that occur without a change in primary DNA sequence. The 2009 Gordon Conference in Epigenetics will feature discussion of various epigenetic phenomena, emerging understanding of their underlying mechanisms, and the growing appreciation that human, animal, and plant health all depend on proper epigenetic control. Special emphasis will be placed on genome-environment interactions particularly as they relate to human disease. Towards improving knowledge of molecular mechanisms, the conference will feature international leaders studying the roles of higher order chromatin structure, noncoding RNA, repeat elements, nuclear organization, and morphogenic evolution. Traditional and new model organisms are selected from plants, fungi, and metazoans.
Yadav, Chandra Bhan; Pandey, Garima; Muthamilarasan, Mehanathan; Prasad, Manoj
The genetic material DNA in association with histone proteins forms the complex structure called chromatin, which is prone to undergo modification through certain epigenetic mechanisms including cytosine DNA methylation, histone modifications, and small RNA-mediated methylation. Alterations in chromatin structure lead to inaccessibility of genomic DNA to various regulatory proteins such as transcription factors, which eventually modulates gene expression. Advancements in high-throughput sequencing technologies have provided the opportunity to study the epigenetic mechanisms at genome-wide levels. Epigenomic studies using high-throughput technologies will widen the understanding of mechanisms as well as functions of regulatory pathways in plant genomes, which will further help in manipulating these pathways using genetic and biochemical approaches. This technology could be a potential research tool for displaying the systematic associations of genetic and epigenetic variations, especially in terms of cytosine methylation onto the genomic region in a specific cell or tissue. A comprehensive study of plant populations to correlate genotype to epigenotype and to phenotype, and also the study of methyl quantitative trait loci (QTL) or epiGWAS, is possible by using high-throughput sequencing methods, which will further accelerate molecular breeding programs for crop improvement. Graphical Abstract.
Oomen, Marlies E; Dekker, Job
While chromatin characteristics in interphase are widely studied, characteristics of mitotic chromatin and their inheritance through mitosis are still poorly understood. During mitosis, chromatin undergoes dramatic changes: transcription stalls, chromatin-binding factors leave the chromatin, histone modifications change and chromatin becomes highly condensed. Many key insights into mitotic chromosome state and conformation have come from extensive microscopy studies over the last century. Over the last decade, the development of 3C-based techniques has enabled the study of higher order chromosome organization during mitosis in a genome-wide manner. During mitosis, chromosomes lose their cell type-specific and locus-dependent chromatin organization that characterizes interphase chromatin and fold into randomly positioned loop arrays. Upon exit of mitosis, cells are capable of quickly rearranging the chromosome conformation to form the cell type-specific interphase organization again. The information that enables this rearrangement after mitotic exit is thought to be encoded at least in part in mitotic bookmarks, e.g. histone modifications and variants, histone remodelers, chromatin factors, and non-coding RNA. Here we give an overview of the chromosomal organization and epigenetic characteristics of interphase and mitotic chromatin in vertebrates. Second, we describe different ways in which mitotic bookmarking enables epigenetic memory of the features of interphase chromatin through mitosis. And third, we explore the role of epigenetic modifications and mitotic bookmarking in cell differentiation.
Qureshi, Irfan A; Mehler, Mark F
Epigenetic mechanisms act as control systems for modulating genomic structure and activity in response to evolving profiles of cell-extrinsic, cell-cell, and cell-intrinsic signals. These dynamic processes are responsible for mediating cell- and tissue-specific gene expression and function and gene-gene and gene-environmental interactions. The major epigenetic mechanisms include DNA methylation and hydroxymethylation; histone protein posttranslational modifications, nucleosome remodeling/repositioning, and higher-order chromatin reorganization; noncoding RNA regulation; and RNA editing. These mechanisms are intimately involved in executing fundamental genomic programs, including gene transcription, posttranscriptional RNA processing and transport, translation, X-chromosome inactivation, genomic imprinting, retrotransposon regulation, DNA replication, and DNA repair and the maintenance of genomic stability. For the nervous system, epigenetics offers a novel and robust framework for explaining how brain development and aging occur, neural cellular diversity is generated, synaptic and neural network connectivity and plasticity are mediated, and complex cognitive and behavioral phenotypes are inherited transgenerationally. Epigenetic factors and processes are, not surprisingly, implicated in nervous system disease pathophysiology through several emerging paradigms - mutations and genetic variation in genes encoding epigenetic factors; impairments in epigenetic factor expression, localization, and function; epigenetic mechanisms modulating disease-associated factors and pathways; and the presence of deregulated epigenetic profiles in central and peripheral tissues. Copyright © 2018 Elsevier B.V. All rights reserved.
Keating, Samuel T; Plutzky, Jorge; El-Osta, Assam
Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biologic memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. While the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes, and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease. PMID:27230637
Schones, Dustin E; Leung, Amy; Natarajan, Rama
The incidence of obesity across the globe has doubled over the past several decades, leading to escalating rates of diabetes mellitus, cardiovascular disease, and other complications. Given this dramatic rise in disease incidence, understanding the cause of these diseases is therefore of paramount importance. Metabolic diseases, such as obesity and diabetes mellitus, result from a multitude of genetic and environmental factors. Although the genetic basis of these diseases has been extensively studied, the molecular pathways whereby environmental factors influence disease progression are only beginning to be understood. One manner by which environmental factors can contribute to disease progression is through modifications to chromatin. The highly structured packaging of the genome into the nucleus through chromatin has been shown to be fundamental to tissue-specific gene regulation. Modifications to chromatin can regulate gene expression and are involved in a myriad of biological functions, and hence, disruption of these modifications is central to many human diseases. These modifications can furthermore be epigenetic in nature, thereby contributing to prolonged disease risk. Recent work has demonstrated that modifications to chromatin are associated with the progression of both diabetes mellitus and obesity, which is the subject of this review. © 2015 American Heart Association, Inc.
Bergmann, Jan H; Martins, Nuno M C; Larionov, Vladimir; Masumoto, Hiroshi; Earnshaw, William C
The centromere is a specialized chromosomal region that serves as the assembly site of the kinetochore. At the centromere, CENP-A nucleosomes form part of a chromatin landscape termed centrochromatin. This chromatin environment conveys epigenetic marks regulating kinetochore formation. Recent work sheds light on the intricate relationship between centrochromatin state, the CENP-A assembly pathway and the maintenance of centromere function. Here, we review the emerging picture of how chromatin affects mammalian kinetochore formation. We place particular emphasis on data obtained from Human Artificial Chromosome (HAC) biology and the targeted engineering of centrochromatin using synthetic HACs. We discuss implications of these findings, which indicate that a delicate balance of histone modifications and chromatin state dictates both de novo centromere formation and the maintenance of centromere identity in dividing cell populations.
Salwen Helen R
Full Text Available Abstract Background Epigenetic aberrations and a CpG island methylator phenotype have been shown to be associated with poor outcomes in children with neuroblastoma (NB. Seven cancer related genes (THBS-1, CASP8, HIN-1, TIG-1, BLU, SPARC, and HIC-1 that have been shown to have epigenetic changes in adult cancers and play important roles in the regulation of angiogenesis, tumor growth, and apoptosis were analyzed to investigate the role epigenetic alterations play in determining NB phenotype. Methods Two NB cell lines (tumorigenic LA1-55n and non-tumorigenic LA1-5s that differ in their ability to form colonies in soft agar and tumors in nude mice were used. Quantitative RNA expression analyses were performed on seven genes in LA1-5s, LA1-55n and 5-Aza-dC treated LA1-55n NB cell lines. The methylation status around THBS-1, HIN-1, TIG-1 and CASP8 promoters was examined using methylation specific PCR. Chromatin immunoprecipitation assay was used to examine histone modifications along the THBS-1 promoter. Luciferase assay was used to determine THBS-1 promoter activity. Cell proliferation assay was used to examine the effect of 5-Aza-dC on NB cell growth. The soft agar assay was used to determine the tumorigenicity. Results Promoter methylation values for THBS-1, HIN-1, TIG-1, and CASP8 were higher in LA1-55n cells compared to LA1-5s cells. Consistent with the promoter methylation status, lower levels of gene expression were detected in the LA1-55n cells. Histone marks associated with repressive chromatin states (H3K9Me3, H3K27Me3, and H3K4Me3 were identified in the THBS-1 promoter region in the LA1-55n cells, but not the LA1-5s cells. In contrast, the three histone codes associated with an active chromatin state (acetyl H3, acetyl H4, and H3K4Me3 were present in the THBS-1 promoter region in LA1-5s cells, but not the LA1-55n cells, suggesting that an accessible chromatin structure is important for THBS-1 expression. We also show that 5-Aza
Maze, Ian; Nestler, Eric J
Drug-induced alterations in gene expression throughout the reward circuitry of the brain are likely components of the persistence of the drug-addicted state. Recent studies examining the molecular mechanisms controlling drug-induced transcriptional, behavioral, and synaptic plasticity have indicated a direct role for chromatin remodeling in the regulation and stability of drug-mediated neuronal gene programs, and the subsequent promulgation of addictive behaviors. In this review, we discuss recent advances in our understanding of chromatin phenomena--or epigenetics, by one definition--that contribute to drug addiction, with the hope that such mechanistic insights may aid in the development of novel therapeutics for future treatments of addiction. © 2011 New York Academy of Sciences.
Full Text Available BACKGROUND: The ability to reprogram mature cells to an embryonic-like state by nuclear transfer or by inducing the expression of key transcription factors has provided us with critical opportunities to linearly map the epigenetic parameters that are essential for attaining pluripotency. CONTENT: Epigenetic reprogramming describes a switch in gene expression of one kind of cell to that of another unrelated cell type. Early studies in frog cloning provided some of the first experimental evidence for reprogramming. Subsequent procedures included mammalian somatic cell nuclear transfer, cell fusion, induction of pluripotency by ectopic gene expression, and direct reprogramming. Through these methods it becomes possible to derive one kind of specialized cell (such as a brain cell from another, more accessible tissue, such as skin in the same individual. This has potential applications for cell replacement without the immunosuppression treatments commonly required when cells are transferred between genetically different individuals. SUMMARY: Reprogramming with transcription factors offers tremendous promise for the future development of patient-specific pluripotent cells and for studies of human disease. The identification of optimized protocols for the differentiation of iPS cells and ES cells into multiple functional cell types in vitro and their proper engraftment in vivo will be challenged in the coming years. Given that the first small molecule approaches aimed at activating pluripotency genes have already been devised and that murine iPS cells have recently been derived by using non-integrative transient expression strategies of the reprogramming factors, we expect that human iPS cells without permanent genetic alterations will soon be generated. KEYWORDS: epigenetics, reprogramming, pluripotency, stem cells, iPS cells, chromatin, DNA methylation.
Full Text Available The long-term effects of behaviour and environmental exposures, particularly during childhood, on health outcomes are well documented. Particularly thought provoking is the notion that exposures to different social environments have a long-lasting impact on human physical health. However, the mechanisms mediating the effects of the environment are still unclear. In the last decade, the main focus of attention was the genome, and interindividual genetic polymorphisms were sought after as the principal basis for susceptibility to disease. However, it is becoming clear that recent dramatic increases in the incidence of certain human pathologies, such as asthma and type 2 diabetes, cannot be explained just on the basis of a genetic drift. It is therefore extremely important to unravel the molecular links between the "environmental" exposure, which is believed to be behind this emerging incidence in certain human pathologies, and the disease's molecular mechanisms. Although it is clear that most human pathologies involve long-term changes in gene function, these might be caused by mechanisms other than changes in the deoxyribonucleic acid (DNA sequence. The genome is programmed by the epigenome, which is composed of chromatin and a covalent modification of DNA by methylation. It is postulated here that "epigenetic" mechanisms mediate the effects of behavioural and environmental exposures early in life, as well as lifelong environmental exposures and the susceptibility to disease later in life. In contrast to genetic sequence differences, epigenetic aberrations are potentially reversible, raising the hope for interventions that will be able to reverse deleterious epigenetic programming.
Jasencakova, Zusana; Groth, Anja
present on new and parental histones and how they influence genome stability and restoration of epigenetically defined domains. Newly deposited histones must change their signature in the process of chromatin restoration, this may occur in a step-wise fashion involving replication-coupled processes...... replication and chromatin assembly processes in time and space. Dynamic recycling and de novo deposition of histones are fundamental for chromatin restoration. Histone post-translational modifications (PTMs) are thought to have a causal role in establishing distinct chromatin structures. Here we discuss PTMs...
Zhang, Zhiying; Alexanian, Arshak R
Mesenchymal stem cells (MSCs) in their immature state express a variety of genes of the three germ layers at relatively low or moderate levels that might explain their phenomenal plasticity. Numerous recent studies have demonstrated that under the appropriate conditions in vitro and in vivo the expression of different sets of these genes can be upregulated, turning MSCs into variety of cell lineages of mesodermal, ectodermal and endodermal origin. While transdifferentiation of MSCs is still controversial, these unique properties make MSCs an ideal autologous source of easily reprogrammable cells. Recently, using the approach of cell reprogramming by biological active compounds that interfere with chromatin structure and function, as well as with specific signalling pathways that promote neural fate commitment, we have been able to generate neural-like cells from human bone marrow (BM)-derived MSCs (hMSCs). However, the efficiency of neural transformation of hMSCs induced by this approach gradually declined with passaging. To elucidate the mechanisms that underlie the higher plasticity of early-passage hMSCs, comparative analysis of the expression levels of several pluripotent and neural genes was conducted for early- and late-passage hMSCs. The results demonstrated that early-passage hMSCs expressed the majority of these genes at low and moderate levels that gradually declined at late passages. Neural induction further increased the expression of some of these genes in hMSCs, accompanied by morphological changes into neural-like cells. We concluded that low and moderate expression of several pluripotent and neural genes in early-passage hMSCs could explain their higher plasticity and pliability for neural induction. Copyright © 2012 John Wiley & Sons, Ltd.
Gabory, Anne; Attig, Linda; Junien, Claudine
The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result in modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, position and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects on a small number o...
Barua, Subit; Junaid, Mohammed A
Rapidly growing evidences link maternal lifestyle and prenatal factors with serious health consequences and diseases later in life. Extensive epidemiological studies have identified a number of factors such as diet, stress, gestational diabetes, exposure to tobacco and alcohol during gestation as influencing normal fetal development. In light of recent discoveries, epigenetic mechanisms such as alteration of DNA methylation, chromatin modifications and modulation of gene expression during gestation are believed to possibly account for various types of plasticity such as neural tube defects, autism spectrum disorder, congenital heart defects, oral clefts, allergies and cancer. The purpose of this article is to review a number of published studies to fill the gap in our understanding of how maternal lifestyle and intrauterine environment influence molecular modifications in the offspring, with an emphasis on epigenetic alterations. To support these associations, we highlighted laboratory studies of rodents and epidemiological studies of human based on sampling population cohorts.
Gigek, Carolina Oliveira; Chen, Elizabeth Suchi; Calcagno, Danielle Queiroz; Wisnieski, Fernanda; Burbano, Rommel Rodriguez; Smith, Marilia Arruda Cardoso
Cancer is considered one of the major health issues worldwide, and gastric cancer accounted for 8% of total cases and 10% of total deaths in 2008. Gastric cancer is considered an age-related disease, and the total number of newly diagnosed cases has been increasing as a result of the higher life expectancy. Therefore, the basic mechanisms underlying gastric tumorigenesis is worth investigation. This review provides an overview of the epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling complex and miRNA, involved in gastric cancer. As the studies in gastric cancer continue, the mapping of an epigenome code is not far for this disease. In conclusion, an epigenetic therapy might appear in the not too distant future.
Renthal, William; Nestler, Eric J
Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.
Takeshima, Hideyuki; Niwa, Tohru; Takahashi, Takamasa; Wakabayashi, Mika; Yamashita, Satoshi; Ando, Takayuki; Inagawa, Yuki; Taniguchi, Hirokazu; Katai, Hitoshi; Sugiyama, Toshiro; Kiyono, Tohru; Ushijima, Toshikazu
A field for cancerization, or a field defect, is formed by the accumulation of genetic and epigenetic alterations in normal-appearing tissues, and is involved in various cancers, especially multiple cancers. Epigenetic alterations are frequently present in chronic inflammation-exposed tissues, but information on individual genes involved in the formation of a field defect is still fragmental. Here, using non-cancerous gastric tissues of cancer patients, we isolated 16 aberrantly methylated genes, and identified chromatin remodelers ACTL6B and SMARCA1 as novel genes frequently methylated in non-cancerous tissues. SMARCA1 was expressed at high levels in normal gastric tissues, but was frequently silenced by aberrant methylation in gastric cancer cells. Moreover, somatic mutations of additional chromatin remodelers, such as ARID1A, SMARCA2, and SMARCA4, were found in 30% of gastric cancers. Mutant allele frequency suggested that the majority of cancer cells harbored a mutation when present. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, in cancer cell lines promoted their growth. These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis and are frequently involved in the formation of a field defect. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Full Text Available Non-alcoholic fatty liver disease (NAFLD, characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC. The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
Tian, Yuan; Mok, Myth T S; Yang, Pengyuan; Cheng, Alfred S L
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
Full Text Available Evidence suggests that human sperm chromatin anomalies adversely affect reproductive outcomesand infertile men possess substantially amount of sperm with chromatin anomalies than fertilemen.Routine semen analysis evaluates parameters such as sperm motility and morphology, but doesnot examine the nuclear DNA integrity of spermatozoa. It has been suggested that altered nuclearchromatin structure or damaged DNA in spermatozoa could modify the special cellular functionsof human spermatozoa, and thereby affect the fertility potential. Intra-cytoplasmic sperm injection(ICSI bypass the barriers to fertilization for such a sperm, then the effect of chromatin anomalies onthe development remains a concern. Therefore, it is essential to develop and use accurate diagnostictests, which may provide better prognostic capabilities than the standard sperm assessments. Thisreview discusses our current understanding of the structure and organization of sperm DNA,the different procedures for assessment of sperm chromatin anomalies including comet assay,Chromomycin A3 (CMA3, sperm chromatin structure assay (SCSA, acridine orange test (AOT,terminal TdT-mediated dUTP-nick-end labelling (TUNEL assay, aniline blue and sperm chromatindispersion (SCD test and the impact of chromatin anomalies on reproductive outcome.
Wang, Jingjing; Zhou, Yincong; Li, Xue; Meng, Xianwen; Fan, Miao; Chen, Hongjun; Xue, Jitong; Chen, Ming
The three-dimensional shapes of chromosomes regulate gene expression and genome function. Our knowledge of the role of chromatin interaction is evolving rapidly. Here, we present a study of global chromatin interaction patterns in Arabidopsis thaliana. High-throughput experimental techniques have been developed to map long-range interactions within chromatin. We have integrated data from multiple experimental sources including Hi-C, BS-seq, ChIP-chip and ChIP-seq data for 17 epigenetic marks and 35 transcription factors. We identified seven groups of interacting loci, which can be distinguished by their epigenetic profiles. Furthermore, the seven groups of interacting loci can be divided into three types of chromatin linkages based on expression status. We observed that two interacting loci sometimes share common epigenetic and transcription factor-binding profiles. Different groups of loci display very different relationships between epigenetic marks and the binding of transcription factors. Distinctive types of chromatin linkages exhibit different gene expression profiles. Our study unveils an entirely unexplored regulatory interaction, linking epigenetic profiles, transcription factor binding and the three-dimensional spatial organization of the Arabidopsis nuclear genome. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: firstname.lastname@example.org.
Moore, David S
Why do we grow up to have the traits we do? Most 20th century scientists answered this question by referring only to our genes and our environments. But recent discoveries in the emerging field of behavioral epigenetics have revealed factors at the interface between genes and environments that also play crucial roles in development. These factors affect how genes work; scientists now know that what matters as much as which genes you have (and what environments you encounter) is how your genes are affected by their contexts. The discovery that what our genes do depends in part on our experiences has shed light on how Nature and Nurture interact at the molecular level inside of our bodies. Data emerging from the world's behavioral epigenetics laboratories support the idea that a person's genes alone cannot determine if, for example, he or she will end up shy, suffering from cardiovascular disease, or extremely smart. Among the environmental factors that can influence genetic activity are parenting styles, diets, and social statuses. In addition to influencing how doctors treat diseases, discoveries about behavioral epigenetics are likely to alter how biologists think about evolution, because some epigenetic effects of experience appear to be transmissible from generation to generation. This domain of research will likely change how we think about the origins of human nature. WIREs Syst Biol Med 2017, 9:e1333. doi: 10.1002/wsbm.1333 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.
Full Text Available Development of psychiatric diseases such as posttraumatic stress disorder (PTSD invokes, as with most complex diseases, both genetic and environmental factors. The era of genome-wide high throughput technologies has sparked the initiation of genotype screenings in large cohorts of diseased and control individuals, but had limited success in identification of disease causing genetic variants. It has become evident that these efforts at the genomic level need to be complemented with endeavours in elucidating the proteome, transcriptome and epigenetic profiles. Epigenetics is attractive in particular because there is accumulating evidence that the lasting impact of adverse life events is reflected in certain covalent modifications of the chromatin.
Wang, Xian huo; Zhao, Xiu juan; Qiu, Li hua; Wang, Hua qing; Wang, Xi
Cancer is a leading cause of death worldwide and the total number of cases globally keeps increasing. For many years, cancer has been thought to be caused by a series of DNA sequence alterations and thus is thought to be a "genetic" disease. However, studies in the last decade, including the large-scale cancer genomics projects, have highlighted the rising importance of epigenetic regulation in cancer. Here, we review recent advances in understanding how chromatin-based epigenetic regulation participates in tumorigenesis and discuss the growing implications of these advances for developing novel strategies to prevent, diagnose, as well as treat cancer.
K C Lakshmaiah
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.
Djuric, Ugljesa; Ellis, James
Induction of pluripotency from somatic cells by exogenous transcription factors is made possible by a variety of epigenetic changes that take place during the reprogramming process. The derivation of fully reprogrammed induced pluripotent stem (iPS) cells is achieved through establishment of embryonic stem cell (ESC)-like epigenetic architecture permitting the reactivation of key endogenous pluripotency-related genes, establishment of appropriate bivalent chromatin domains and DNA hypomethylation of genomic heterochromatic regions. Restructuring of the epigenetic landscape, however, is a very inefficient process and the vast majority of the induced cells fail to complete the reprogramming process. Optimal ESC-like epigenetic reorganization is necessary for all reliable downstream uses of iPS cells, including in vitro modeling of disease and clinical applications. Here, we discuss the key advancements in the understanding of dynamic epigenetic changes taking place over the course of the reprogramming process and how aberrant epigenetic remodeling may impact downstream applications of iPS cell technology.
Miozzo, Monica; Vaira, Valentina; Sirchia, Silvia Maria
Based on the pivotal importance of epigenetics for transcription regulation, it is not surprising that cancer is characterized by several epigenetic abnormalities. Conversely to genetic alterations, epigenetic changes are not permanent, thus represent opportunities for therapeutic strategies designed to reverse transcriptional abnormalities, and cancer is the first disease in which epigenetic therapies with chromatin remodeling agents were introduced. The role of miRNAs in gene regulation supports their potential as innovative therapeutic strategy. Recent evidences have proven that the environment can profoundly influence the epigenome: diet, smoking and alcohol consumption can negatively impact the expression profile. Given the plasticity of epigenetic marks, it is challenging the idea that the epigenetic alterations are 'druggable' sites using specific food components.
Full Text Available Advances in genomic studies have led to significant progress in understanding the epigenetically controlled interplay between chromatin structure and nuclear functions. Epigenetic modifications were shown to play a key role in transcription regulation and genome activity during development and differentiation or in response to the environment. Paradoxically, the molecular mechanisms that regulate the initiation and the maintenance of the spatio-temporal replication program in higher eukaryotes, and in particular their links to epigenetic modifications, still remain elusive. By integrative analysis of the genome-wide distributions of thirteen epigenetic marks in the human cell line K562, at the 100 kb resolution of corresponding mean replication timing (MRT data, we identify four major groups of chromatin marks with shared features. These states have different MRT, namely from early to late replicating, replication proceeds though a transcriptionally active euchromatin state (C1, a repressive type of chromatin (C2 associated with polycomb complexes, a silent state (C3 not enriched in any available marks, and a gene poor HP1-associated heterochromatin state (C4. When mapping these chromatin states inside the megabase-sized U-domains (U-shaped MRT profile covering about 50% of the human genome, we reveal that the associated replication fork polarity gradient corresponds to a directional path across the four chromatin states, from C1 at U-domains borders followed by C2, C3 and C4 at centers. Analysis of the other genome half is consistent with early and late replication loci occurring in separate compartments, the former correspond to gene-rich, high-GC domains of intermingled chromatin states C1 and C2, whereas the latter correspond to gene-poor, low-GC domains of alternating chromatin states C3 and C4 or long C4 domains. This new segmentation sheds a new light on the epigenetic regulation of the spatio-temporal replication program in human and
Julienne, Hanna; Zoufir, Azedine; Audit, Benjamin; Arneodo, Alain
Advances in genomic studies have led to significant progress in understanding the epigenetically controlled interplay between chromatin structure and nuclear functions. Epigenetic modifications were shown to play a key role in transcription regulation and genome activity during development and differentiation or in response to the environment. Paradoxically, the molecular mechanisms that regulate the initiation and the maintenance of the spatio-temporal replication program in higher eukaryotes, and in particular their links to epigenetic modifications, still remain elusive. By integrative analysis of the genome-wide distributions of thirteen epigenetic marks in the human cell line K562, at the 100 kb resolution of corresponding mean replication timing (MRT) data, we identify four major groups of chromatin marks with shared features. These states have different MRT, namely from early to late replicating, replication proceeds though a transcriptionally active euchromatin state (C1), a repressive type of chromatin (C2) associated with polycomb complexes, a silent state (C3) not enriched in any available marks, and a gene poor HP1-associated heterochromatin state (C4). When mapping these chromatin states inside the megabase-sized U-domains (U-shaped MRT profile) covering about 50% of the human genome, we reveal that the associated replication fork polarity gradient corresponds to a directional path across the four chromatin states, from C1 at U-domains borders followed by C2, C3 and C4 at centers. Analysis of the other genome half is consistent with early and late replication loci occurring in separate compartments, the former correspond to gene-rich, high-GC domains of intermingled chromatin states C1 and C2, whereas the latter correspond to gene-poor, low-GC domains of alternating chromatin states C3 and C4 or long C4 domains. This new segmentation sheds a new light on the epigenetic regulation of the spatio-temporal replication program in human and provides a
McDevitt, Michael A
Aberrant DNA methylation is frequent in the myeloid malignancies, particularly myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Promoter CpG methylation is correlated with silencing of tumor-suppressor genes (TSGs) in specific pathways that are also targets of mutation or other mechanisms of inactivation, and is thought to contribute to disease progression and poor prognosis. Epigenetic contributions to myeloid pathogenesis are more complex. Examples include TSG inactivation and oncogenic activation associated with formation of altered chromatin separate from CpG methylation. Epigenetic dysregulation occurs at multiple disease stages and at non-CpG island genomic sites, and also includes genomic hypomethylation and small RNA mechanisms of epigenetic regulation. Identification of recurrent mutations in potential epigenetic regulators, including TET2, IDH1, IDH2, DNMT3A, UTX, and ASXL1, were recently described. Accordingly, therapeutics directed towards epigenetic mechanisms including methylation inhibitors and histone deacetylase (HDAC) inhibitors have had some clinical success when applied to MDS and AML. However, identification of the underlying mechanisms associated with clinical responses and drug resistance remain enigmatic. Remarkably, in spite of significant molecular and translational progress, there are currently no epigenetic biomarkers in widespread clinical use. In this review, we explore the potential applications of epigenetic biomarker discovery, including epigenetic profiling for myeloid malignancy pathogenesis understanding, diagnostic classification, and development of effective treatment paradigms for these generally considered poor prognosis disorders. Copyright © 2012. Published by Elsevier Inc.
Ntziachristos, Panagiotis; Mullenders, Jasper; Trimarchi, Thomas; Aifantis, Iannis
Over the past decade, it has become clear that both genetics and epigenetics play pivotal roles in cancer onset and progression. The importance of epigenetic regulation in proper maintenance of cellular state is highlighted by the frequent mutation of chromatin modulating factors across cancer subtypes. Identification of these mutations has created an interest in designing drugs that target enzymes involved in DNA methylation and posttranslational modification of histones. In this review, we ...
Jasencakova, Zusana; Groth, Anja
-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor-promoting insults is recognized as a significant source...... of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis....
Remely, Marlene; de la Garza, Ana Laura; Magnet, Ulrich; Aumueller, Eva; Haslberger, Alexander G
Genetic and environmental factors, especially nutrition and lifestyle, have been discussed in the literature for their relevance to epidemic obesity. Gene-environment interactions may need to be understood for an improved understanding of the causes of obesity, and epigenetic mechanisms are of special importance. Consequences of epigenetic mechanisms seem to be particularly important during certain periods of life: prenatal, postnatal and intergenerational, transgenerational inheritance are discussed with relevance to obesity. This review focuses on nutrients, diet and habits influencing intergenerational, transgenerational, prenatal and postnatal epigenetics; on evidence of epigenetic modifiers in adulthood; and on animal models for the study of obesity.
Full Text Available The centromere is a specialized chromosomal region identified as the major constriction, upon which the kinetochore complex is formed, ensuring accurate chromosome orientation and segregation during cell division. The rapid evolution of centromere DNA sequence and the conserved centromere function are two contradictory aspects of centromere biology. Indeed, the sole presence of genetic sequence is not sufficient for centromere formation. Various dicentric chromosomes with one inactive centromere have been recognized. It has also been found that de novo centromere formation is common on fragments in which centromeric DNA sequences are lost. Epigenetic factors play important roles in centromeric chromatin assembly and maintenance. Nondisjunction of the supernumerary B chromosome early prophase of meiosis I requires an active centromere. This review discusses recent studies in maize about genetic and epigenetic elements regulating formation and maintenance of centromere chromatin, as well as centromere behavior in meiosis.
van Dijk, S J; Molloy, P L; Varinli, H; Morrison, J L; Muhlhausler, B S
Recent technological advances in epigenome profiling have led to an increasing number of studies investigating the role of the epigenome in obesity. There is also evidence that environmental exposures during early life can induce persistent alterations in the epigenome, which may lead to an increased risk of obesity later in life. This paper provides a systematic review of studies investigating the association between obesity and either global, site-specific or genome-wide methylation of DNA. Studies on the impact of pre- and postnatal interventions on methylation and obesity are also reviewed. We discuss outstanding questions, and introduce EpiSCOPE, a multidisciplinary research program aimed at increasing the understanding of epigenetic changes in emergence of obesity. An electronic search for relevant articles, published between September 2008 and September 2013 was performed. From the 319 articles identified, 46 studies were included and reviewed. The studies provided no consistent evidence for a relationship between global methylation and obesity. The studies did identify multiple obesity-associated differentially methylated sites, mainly in blood cells. Extensive, but small, alterations in methylation at specific sites were observed in weight loss intervention studies, and several associations between methylation marks at birth and later life obesity were found. Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Eventually this may help in predicting an individual's obesity risk at a young age and opens possibilities for introducing targeted prevention strategies. It has also become clear that several epigenetic marks are modifiable, by changing the exposure in utero, but also by lifestyle changes in adult life, which implies that there is the potential for interventions to be introduced in postnatal life to modify
Casanello, Paola; Krause, Bernardo J; Castro-Rodríguez, José A; Uauy, Ricardo
Current evidence supports the notion that exposure to various environmental conditions in early life may induce permanent changes in the epigenome that persist throughout the life-course. This article focuses on early changes associated with obesity in adult life. A review is presented on the factors that induce changes in whole genome (DNA) methylation in early life that are associated with adult onset obesity and related disorders. In contrast, reversal of epigenetic changes associated with weight loss in obese subjects has not been demonstrated. This contrasts with well-established associations found between obesity related DNA methylation patterns at birth and adult onset obesity and diabetes. Epigenetic markers may serve to screen indivuals at risk for obesity and assess the effects of interventions in early life that may delay or prevent obesity in early life. This might contribute to lower the obesity-related burden of death and disability at the population level. The available evidence indicates that epigenetic marks are in fact modifiable, based on modifications in the intrauterine environment and changes in food intake, physical activity and dietary patterns patterns during pregnancy and early years of adult life. This offers the opportunity to intervene before conception, during pregnancy, infancy, childhood, and also in later life. There must be documentation on the best preventive actions in terms of diet and physical activity that will modify or revert the adverse epigenetic markers, thus preventing obesity and diabetes in suceptible individuals and populations. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.
Vermeulen, Michiel; Eberl, H Christian; Matarese, Filomena
Trimethyl-lysine (me3) modifications on histones are the most stable epigenetic marks and they control chromatin-mediated regulation of gene expression. Here, we determine proteins that bind these marks by high-accuracy, quantitative mass spectrometry. These chromatin "readers" are assigned......-lysine sites by specialized complexes appears to be a widespread mechanism to mediate gene expression....
Jachowicz, Joanna W; Bing, Xinyang; Pontabry, Julien; Bošković, Ana; Rando, Oliver J; Torres-Padilla, Maria-Elena
After fertilization, to initiate development, gametes are reprogramed to become totipotent. Approximately half of the mammalian genome consists of repetitive elements, including retrotransposons, some of which are transcribed after fertilization. Retrotransposon activation is generally assumed to be a side effect of the extensive chromatin remodeling underlying the epigenetic reprogramming of gametes. Here, we used a targeted epigenomic approach to address whether specific retrotransposon families play a direct role in chromatin organization and developmental progression. We demonstrate that premature silencing of LINE-1 elements decreases chromatin accessibility, whereas prolonged activation prevents the gradual chromatin compaction that occurs naturally in developmental progression. Preventing LINE-1 activation and interfering with its silencing decreases developmental rates independently of the coding nature of the LINE-1 transcript, thus suggesting that LINE-1 functions primarily at the chromatin level. Our data suggest that activation of LINE-1 regulates global chromatin accessibility at the beginning of development and indicate that retrotransposon activation is integral to the developmental program.
Underhill, Alan; Hendzel, Michael J
In recognition of Canada's longstanding interest in epigenetics - and a particular linguistic interjection - the inaugural 'Epigenetics, Eh!' conference was held between 4-7 May 2011 in London, Ontario. The meeting struck an excellent balance between Canadian and international leaders in epigenetic research while also providing a venue to showcase up-and-coming talent. Almost without exception, presentations touched on the wide-ranging and severe consequences of epigenetic dysfunction, as well as current and emerging therapeutic opportunities. While gaining a deeper understanding of how DNA and histone modifications, together with multiple classes of ncRNAs, act to functionalize our genome, participants were also provided with a glimpse of the astounding complexity of chromatin structure, challenging existing dogma.
Beata M. Gruber
Full Text Available Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethylation and the transcriptionally non-active sequences are hypermethylated. Covalent histone modifications and DNA methylation are correlated and interacting. Chromatin modeling is regulated not only by specific enzymes but also by protein kinases or phosphatases and coactivators, such as CBP. Such interaction makes the “histone code” which with the chromatin proteins determines gene expression patterns as the response to external agents. Evidence of a major role for epigenetic modifications in neurological disease has come from three converging lines of enquiry: high conservation throughout evolution of the histone residues that are the target for epigenetic modifications; association between mutations in epigenetic components and multisystem disease syndrome in the nervous system; and broad efficacy of small-molecule epigenetic modulators, e.g. histone deacetylase inhibitors, in models of neurological diseases incurable up to now, such as Huntington’s disease, (HD, Parkinson’s disease (PD and Alzheimer’s disease (AD. This article is a survey of the literature concerning the characterization of gene expression patterns correlated with some neurodegenerative diseases. The processes of DNA hypomethylation and histone acetylation are emphasized. The histone deacetylases are indicated as the basis for design of potential drugs.
Marpadga A. Reddy
Full Text Available Diabetic nephropathy (DN is a major complication associated with both type 1 and type 2 diabetes, and a leading cause of end-stage renal disease. Conventional therapeutic strategies are not fully efficacious in the treatment of DN, suggesting an incomplete understanding of the gene regulation mechanisms involved in its pathogenesis. Furthermore, evidence from clinical trials has demonstrated a “metabolic memory” of prior exposure to hyperglycemia that continues to persist despite subsequent glycemic control. This remains a major challenge in the treatment of DN and other vascular complications. Epigenetic mechanisms such as DNA methylation, nucleosomal histone modifications, and noncoding RNAs control gene expression through regulation of chromatin structure and function and post-transcriptional mechanisms without altering the underlying DNA sequence. Emerging evidence indicates that multiple factors involved in the etiology of diabetes can alter epigenetic mechanisms and regulate the susceptibility to diabetes complications. Recent studies have demonstrated the involvement of histone lysine methylation in the regulation of key fibrotic and inflammatory genes related to diabetes complications including DN. Interestingly, histone lysine methylation persisted in vascular cells even after withdrawal from the diabetic milieu, demonstrating a potential role of epigenetic modifications in metabolic memory. Rapid advances in high-throughput technologies in the fields of genomics and epigenomics can lead to the identification of genome-wide alterations in key epigenetic modifications in vascular and renal cells in diabetes. Altogether, these findings can lead to the identification of potential predictive biomarkers and development of novel epigenetic therapies for diabetes and its associated complications.
Renu A. Kowluru
Full Text Available Diabetic retinopathy remains one of the most debilitating chronic complications, but despite extensive research in the field, the exact mechanism(s responsible for how retina is damaged in diabetes remains ambiguous. Many metabolic pathways have been implicated in its development, and genes associated with these pathways are altered. Diabetic environment also facilitates epigenetics modifications, which can alter the gene expression without permanent changes in DNA sequence. The role of epigenetics in diabetic retinopathy is now an emerging area, and recent work has shown that genes encoding mitochondrial superoxide dismutase (Sod2 and matrix metalloproteinase-9 (MMP-9 are epigenetically modified, activates of epigenetic modification enzymes, histone lysine demethylase 1 (LSD1, and DNA methyltransferase are increased, and the micro RNAs responsible for regulating nuclear transcriptional factor and VEGF are upregulated. With the growing evidence of epigenetic modifications in diabetic retinopathy, better understanding of these modifications has potential to identify novel targets to inhibit this devastating disease. Fortunately, the inhibitors and mimics targeted towards histone modification, DNA methylation, and miRNAs are now being tried for cancer and other chronic diseases, and better understanding of the role of epigenetics in diabetic retinopathy will open the door for their possible use in combating this blinding disease.
Tammen, Stephanie A; Friso, Simonetta; Choi, Sang-Woon
While the eukaryotic genome is the same throughout all somatic cells in an organism, there are specific structures and functions that discern one type of cell from another. These differences are due to the cell's unique gene expression patterns that are determined during cellular differentiation. Interestingly, these cell-specific gene expression patterns can be affected by an organism's environment throughout its lifetime leading to phenotypical changes that have the potential of altering risk of some diseases. Both cell-specific gene expression signatures and environment mediated changes in expression patterns can be explained by a complex network of modifications to the DNA, histone proteins and degree of DNA packaging called epigenetic marks. Several areas of research have formed to study these epigenetic modifications, including DNA methylation, histone modifications, chromatin remodeling and microRNA (miRNA). The original definition of epigenetics incorporates inheritable but reversible phenomena that affect gene expression without altering base pairs. Even though not all of the above listed epigenetic traits have demonstrated heritability, they can all alter gene transcription without modification to the underlying genetic sequence. Because these epigenetic patterns can also be affected by an organism's environment, they serve as an important bridge between life experiences and phenotypes. Epigenetic patterns may change throughout one's lifespan, by an early life experience, environmental exposure or nutritional status. Epigenetic signatures influenced by the environment may determine our appearance, behavior, stress response, disease susceptibility, and even longevity. The interaction between types of epigenetic modifications in response to environmental factors and how environmental cues affect epigenetic patterns will further elucidate how gene transcription can be affectively altered. Copyright © 2012 Elsevier Ltd. All rights reserved.
Volokh, O I; Derkacheva, N I; Studitsky, V M; Sokolova, O S
Changes of chromatin structure require participation of chromatin remodeling factors (CRFs), which are ATP-dependent multisubunit complexes that change the structure of the nucleosome without covalently modifying its components. CRFs act together with other protein factors to regulate the extent of chromatin condensation. Four CRF families are currently distinguished based on their structural and biochemical characteristics: SWI/SNF, ISWI, Mi-2/CHD, and SWR/INO80. X-ray diffraction analysis and electron microscopy are the main methods to obtain structural information about macromolecules. CRFs are difficult to obtain in crystal because of their large sizes and structural heterogeneity, and transmission electron microscopy (TEM) is mostly employed in their structural studies. The review considers all structures obtained for CRFs by TEM and discusses several models of CRF-nucleosome interactions.
Ernst, Jason; Kellis, Manolis
A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. Although individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use a multivariate Hidden Markov Model to reveal chromatin states in human T cells, based on recurrent and spatially coherent combinations of chromatin marks.We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, largescale repressed and repeat-associated states. Each chromatin state shows specific enrichments in functional annotations, sequence motifs and specific experimentally observed characteristics, suggesting distinct biological roles. This approach provides a complementary functional annotation of the human genome that reveals the genome-wide locations of diverse classes of epigenetic function.
Millan, Mark J
Neurodevelopmental disorders (NDDs) are characterized by aberrant and delayed early-life development of the brain, leading to deficits in language, cognition, motor behaviour and other functional domains, often accompanied by somatic symptoms. Environmental factors like perinatal infection, malnutrition and trauma can increase the risk of the heterogeneous, multifactorial and polygenic disorders, autism and schizophrenia. Conversely, discrete genetic anomalies are involved in Down, Rett and Fragile X syndromes, tuberous sclerosis and neurofibromatosis, the less familiar Phelan-McDermid, Sotos, Kleefstra, Coffin-Lowry and "ATRX" syndromes, and the disorders of imprinting, Angelman and Prader-Willi syndromes. NDDs have been termed "synaptopathies" in reference to structural and functional disturbance of synaptic plasticity, several involve abnormal Ras-Kinase signalling ("rasopathies"), and many are characterized by disrupted cerebral connectivity and an imbalance between excitatory and inhibitory transmission. However, at a different level of integration, NDDs are accompanied by aberrant "epigenetic" regulation of processes critical for normal and orderly development of the brain. Epigenetics refers to potentially-heritable (by mitosis and/or meiosis) mechanisms controlling gene expression without changes in DNA sequence. In certain NDDs, prototypical epigenetic processes of DNA methylation and covalent histone marking are impacted. Conversely, others involve anomalies in chromatin-modelling, mRNA splicing/editing, mRNA translation, ribosome biogenesis and/or the regulatory actions of small nucleolar RNAs and micro-RNAs. Since epigenetic mechanisms are modifiable, this raises the hope of novel therapy, though questions remain concerning efficacy and safety. The above issues are critically surveyed in this review, which advocates a broad-based epigenetic framework for understanding and ultimately treating a diverse assemblage of NDDs ("epigenopathies") lying at the
Martos, Suzanne N.; Tang, Wan-yee; Wang, Zhibin
Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be i...
Full Text Available Charles C Matouk,1 Paul J Turgeon,2 Philip A Marsden2,31Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; 3Keenan Research Centre and Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, CanadaAbstract: Advances in high-throughput genome sequencing and genome-wide association studies indicate that only a fraction of estimated variability in stroke risk can be explained by genetic variation in protein-coding genes alone. Epigenetics is defined as chromatin-based mechanisms important in the regulation of gene expression that do not involve changes in the DNA sequence per se. Epigenetics represents an alternative explanation for how traditional risk factors confer increased stroke risk, provide a newer paradigm to explain heritability not explained by genetic variation, and provide insight into the link between how the environment of a cell can interact with the static DNA code. The nuclear-based mechanisms that contribute to epigenetic gene regulation can be separated into three distinct but highly interrelated processes: DNA methylation and hydroxymethylation; histone density and posttranslational modifications; and RNA-based mechanisms. Together, they offer a newer perspective on transcriptional control paradigms in blood vessels and provide a molecular basis for understanding how the environment impacts the genome to modify stroke susceptibility. This alternative view for transcriptional regulation allows a reassessment of the cis/trans model and even helps explain some of the limitations of current approaches to genetic-based screens. For instance, how does the environment exert chronic effects on gene expression in blood vessels after weeks or years? When a vascular cell divides, how is this information transmitted to daughter cells? This review provides an introduction to epigenetic concepts and a
Karen T Smith
Full Text Available Environments can be ever-changing and stresses are commonplace. In order for organisms to survive, they need to be able to respond to change and adapt to new conditions. Fortunately, many organisms have systems in place that enable dynamic adaptation to immediate stresses and changes within the environment. Much of this cellular response is coordinated by modulating the structure and accessibility of the genome. In eukaryotic cells, the genome is packaged and rolled up by histone proteins to create a series of DNA/histone core structures known as nucleosomes; these are further condensed into chromatin. The degree and nature of the condensation can in turn determine which genes are transcribed. Histones can be modified chemically by a large number of proteins that are thereby responsible for dynamic changes in gene expression. In this Primer we discuss findings from a study published in this issue of PLoS Biology by Weiner et al. that highlight how chromatin structure and chromatin binding proteins alter transcription in response to environmental changes and stresses. Their study reveals the importance of chromatin in mediating the speed and amplitude of stress responses in cells and suggests that chromatin is a critically important component of the cellular response to stress.
Kubiak, Marta; Lewandowska, Marzena Anna
Regulation of gene expression in eukaryotes involves many complex processes, in which chromatin structure plays an important role. In addition to the epigenetic effects, such as DNA methylation and phosphorylation or histone modifications, gene expression is also controlled by the spatial organization of chromatin. For example, distant regulatory elements (enhancers, insulators) may come into direct physical interaction with target genes or other regulatory elements located in genomic regions of up to several hundred kilobases in size. Such long-range interactions result in the formation of chromatin loops. In the last several years, there has been a rapid increase in our knowledge of the spatial organization of chromatin in the nucleus through the chromosome conformation capture (3C) technology. Here we review and compare the original 3C and 3C-based methods including chromosome conformation capture-on-chip (4C), chromosome conformation capture carbon copy (5C), hi-resolution chromosome confomation capture (HiC). In this article, we discuss different aspects of how the nuclear organization of chromatin is associated with gene expression regulation and how this knowledge is useful in translational medicine and clinical applications. We demonstrate that the knowledge of the chromatin 3D organization may help understand the mechanisms of gene expression regulation of genes involved in the development of human diseases, such as CFTR (responsible for cystic fibrosis) or IGFBP3 (associated with breast cancer pathogenesis). Additionally, 3C-derivative methods have been also useful in the diagnosis of some leukemia subtypes.
Greschik, Holger; Schüle, Roland; Günther, Thomas
Epigenetic regulators including writers, erasers, and readers of chromatin marks have been implicated in numerous diseases and are therefore subject of intense academic and pharmaceutical research. While several small-molecule inhibitors targeting writers or erasers are either approved drugs or are currently being evaluated in clinical trials, the targeting of epigenetic readers has lagged behind. Proof-of-principle that epigenetic readers are also relevant drug targets was provided by landmark discoveries of selective inhibitors targeting the BET family of acetyl-lysine readers. More recently, high affinity chemical probes for non-BET acetyl- and methyl-lysine reader domains have also been developed. Areas covered: This article covers recent advances with the identification and validation of inhibitors and chemical probes targeting epigenetic reader domains. Issues related to epigenetic reader druggability, quality requirements for chemical probes, interpretation of cellular action, unexpected cross-talk, and future challenges are also discussed. Expert opinion: Chemical probes provide a powerful means to unravel biological functions of epigenetic readers and evaluate their potential as drug targets. To yield meaningful results, potency, selectivity, and cellular target engagement of chemical probes need to be stringently validated. Future chemical probes will probably need to fulfil additional criteria such as strict target specificity or the targeting of readers within protein complexes.
Ma, Li; Chua, Mei-Sze; Andrisani, Ourania; So, Samuel
Hepatocellular carcinoma (HCC), the predominant form of adult liver malignancies, is a global health concern. Its dismal prognosis has prompted recent significant advances in the understanding of its etiology and pathogenesis. The deregulation of epigenetic mechanisms, which maintain heritable gene expression changes and chromatin organization, is implicated in the development of multiple cancers, including HCC. This review summarizes the current knowledge of epigenetic mechanisms in the pathogenesis of HCC, with an emphasis on HCC mediated by chronic hepatitis B virus infection. This review also discusses the encouraging outcomes and lessons learnt from epigenetic therapies for hematological and other solid cancers, and highlights the future potential of similar therapies in the treatment of HCC.
Szulwach, Keith E.; Jin, Peng
Summary Genomic function is dictated by a combination of DNA sequence and the molecular mechanisms controlling access to genetic information. Access to DNA can be determined by the interpretation of covalent modifications that influence the packaging of DNA into chromatin, including DNA methylation and histone modifications. These modifications are believed to be forms of “epigenetic codes” that exist in discernable combinations that reflect cellular phenotype. Although DNA methylation is known to play important roles in gene regulation and genomic function, its contribution to the encoding of epigenetic information is just beginning to emerge. Here we discuss paradigms associated with the various components of DNA methylation/demethylation and recent advances in the understanding of its dynamic regulation in the genome, integrating these mechanisms into a framework to explain how DNA methylation could contribute to epigenetic codes. PMID:24242211
Chen, Xiangsong; Zhou, Dao-Xiu
During recent years rice genome-wide epigenomic information such as DNA methylation and histone modifications, which are important for genome activity has been accumulated. The function of a number of rice epigenetic regulators has been studied, many of which are found to be involved in a diverse range of developmental and stress-responsive pathways. Analysis of epigenetic variations among different rice varieties indicates that epigenetic modification may lead to inheritable phenotypic variation. Characterizing phenotypic consequences of rice epigenomic variations and the underlining chromatin mechanism and identifying epialleles related to important agronomic traits may provide novel strategies to enhance agronomically favorable traits and grain productivity in rice. Copyright © 2013 Elsevier Ltd. All rights reserved.
Calvanese, Vincenzo; Lara, Ester; Fraga, Mario F
Epigenetics is a new and expanding science that studies the chromatin-based regulation of gene expression. It is achieving considerable importance, especially with regard to developmental mechanisms that drive cell and organ differentiation, as well as in all those biological processes that involve response and adaptation to environmental stimuli. One of the most interesting biological questions concerning animals, especially human beings, is the ability to distinguish self from nonself. This ability has developed throughout evolution, both as the main function of the immune system, which defends against attack by foreign organisms and at the level of consciousness of oneself as an individual, one of the highest functions of the brain that enables social life. Here we will attempt to dissect the epigenetic mechanisms involved in establishing these higher functions and describe some alterations of the epigenetic machinery responsible for the impairment of correct self-recognition and self-identity.
Authors: Marco Antonio Mendoza-Parra, Shankaranarayanan Pattabhiraman & Hinrich Gronemeyer ### Abstract Chromatin immunoprecipitation combined with massive parallel sequencing (ChIP-seq) is increasingly used to study protein-chromatin interactions or local epigenetic modifications at genome-wide scale. ChIP-seq can be performed directly with several ng of immunoprecipitated DNA, which is generally obtained from a several million cells, depending on the quality of the antibody. ChI...
Hansen, Klaus H; Bracken, Adrian P; Pasini, Diego
Organization of chromatin by epigenetic mechanisms is essential for establishing and maintaining cellular identity in developing and adult organisms. A key question that remains unresolved about this process is how epigenetic marks are transmitted to the next cell generation during cell division...... during incorporation of newly synthesized histones. This mechanism ensures maintenance of the H3K27me3 epigenetic mark in proliferating cells, not only during DNA replication when histones synthesized de novo are incorporated, but also outside S phase, thereby preserving chromatin structure...
Benevento, M.; Molengraft, M. van de; Westen, R. van; Bokhoven, H. van; Nadif Kasri, N.
Histone post-translational modifications are key epigenetic processes controlling the regulation of gene transcription. In recent years it has become apparent that chromatin modifications contribute to cognition through the modulation of gene expression required for the expression and consolidation
Jessa, Selin; Kleinman, Claudia L
Chromatin state plays a major role in controlling gene expression, and comparative analysis of ChIP-seq data is key to understanding epigenetic regulation. We present chromswitch, an R/Bioconductor package to integrate epigenomic data in a defined window of interest to detect an overall switch in chromatin state. Chromswitch accurately classifies a benchmarking dataset, and when applied genome-wide, the tool successfully detects chromatin changes that result in brain-specific expression. Chromswitch is implemented as an R package available from Bioconductor at https://bioconductor.org/packages/chromswitch. email@example.com. Supplementary material are available online. All data and code for the analysis presented in this paper are available at https://doi.org/10.5281/zenodo.1101260.
Gene regulatory processes lead to differential gene expression and are referred to as epigenetic phenomena; these are ubiquitous processes in the biological world. These reversible heritable changes concern DNA and RNA, their interactions, and chromatin-mediated and RNA-mediated mechanisms. DNA compaction is ...
Full Text Available Hepatocellular Carcinoma (HCC is one of the most predominant malignancies with high fatality rate. This deadly cancer is rising at an alarming rate because it is quite resistant to radio- and chemotherapy. Different epigenetic mechanisms such as histone modifications, DNA methylation, chromatin remodeling, and expression of noncoding RNAs drive the cell proliferation, invasion, metastasis, initiation, progression, and development of HCC. These epigenetic alterations because of potential reversibility open way towards the development of biomarkers and therapeutics. The contribution of these epigenetic changes to HCC development has not been thoroughly explored yet. Further research on HCC epigenetics is necessary to better understand novel molecular-targeted HCC treatment and prevention. This review highlights latest research progress and current updates regarding epigenetics of HCC, biomarker discovery, and future preventive and therapeutic strategies to combat the increasing risk of HCC.
The Medical Research Council Clinical Sciences Centre Symposium on Epigenetic Regulation: From Mechanism to Intervention in London, UK, which was held on 20-22 June 2012, attracted 305 participants from around the globe and included 37 speakers and 85 selected poster presentations. The organizing committee, led by Niall Dillon of the Medical Research Council Clinical Sciences Centre (London, UK), consisted of several distinguished researchers in the fields of epigenetics and chromatin organization from across the UK. The meeting covered a diverse range of topics and brought together scientists carrying out fundamental research on epigenetic mechanisms and also researchers who are exploring the role of epigenetics in human diseases and its clinical applications. In addition, the meeting highlighted some emerging aspects in the rapidly evolving field of epigenetics.
Prokopuk, Lexie; Western, Patrick S; Stringer, Jessica M
Epigenetic modifications direct the way DNA is packaged into the nucleus, making genes more or less accessible to transcriptional machinery and influencing genomic stability. Environmental factors have the potential to alter the epigenome, allowing genes that are silenced to be activated and vice versa. This ultimately influences disease susceptibility and health in an individual. Furthermore, altered chromatin states can be transmitted to subsequent generations, thus epigenetic modifications may provide evolutionary mechanisms that impact on adaptation to changed environments. However, the mechanisms involved in establishing and maintaining these epigenetic modifications during development remain unclear. This review discusses current evidence for transgenerational epigenetic inheritance, confounding issues associated with its study, and the biological relevance of altered epigenetic states for subsequent generations.
Qureshi, Irfan A; Mehler, Mark F
In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders.
Gabory, Anne; Attig, Linda; Junien, Claudine
The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result in modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, position and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. In parallel, increasing numbers of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. A number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. The existence of a self-propagating epigenetic cycle has been demonstrated. Moreover, recent studies demonstrate an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development during an individual's lifetime or over several generations remains a challenging issue.
Attig, Linda; Gabory, Anne; Junien, Claudine
The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result into modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions and functions of relevant epigenetic marks. Animal models, including mice, rats, sheep, pigs and rabbits, remain a vital tool for studying the influence of early nutritional events on adult health and disease. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. They have demonstrated the existence of a self-propagating epigenetic cycle. In parallel, an increasing number of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. In recent months, a number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development, during an individual's lifetime or over several generations, remains a challenging issue.
Sophie E. Polo
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.
Daniel, Jeremy A; Nussenzweig, André
Chemical modifications to the DNA and histone protein components of chromatin can modulate gene expression and genome stability. Understanding the physiological impact of changes in chromatin structure remains an important question in biology. As one example, in order to generate antibody diversity...... with somatic hypermutation and class switch recombination, chromatin must be made accessible for activation-induced cytidine deaminase (AID)-mediated deamination of cytosines in DNA. These lesions are recognized and removed by various DNA repair pathways but, if not handled properly, can lead to formation...... of oncogenic chromosomal translocations. In this review, we focus the discussion on how chromatin-modifying activities and -binding proteins contribute to the native chromatin environment in which AID-induced DNA damage is targeted and repaired. Outstanding questions remain regarding the direct roles...
Adam, Salomé; Polo, Sophie E.
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
Yan, Huihuang; Tian, Shulan; Slager, Susan L; Sun, Zhifu; Ordog, Tamas
Epigenetic information encoded in covalent modifications of DNA and histone proteins regulates fundamental biological processes through the action of chromatin regulators, transcription factors, and noncoding RNA species. Epigenetic plasticity enables an organism to respond to developmental and environmental signals without genetic changes. However, aberrant epigenetic control plays a key role in pathogenesis of disease. Normal epigenetic states could be disrupted by detrimental mutations and expression alteration of chromatin regulators or by environmental factors. In this primer, we briefly review the epigenetic basis of human disease and discuss how recent discoveries in this field could be translated into clinical diagnosis, prevention, and treatment. We introduce platforms for mapping genome-wide chromatin accessibility, nucleosome occupancy, DNA-binding proteins, and DNA methylation, primarily focusing on the integration of DNA methylation and chromatin immunoprecipitation-sequencing technologies into disease association studies. We highlight practical considerations in applying high-throughput epigenetic assays and formulating analytical strategies. Finally, we summarize current challenges in sample acquisition, experimental procedures, data analysis, and interpretation and make recommendations on further refinement in these areas. Incorporating epigenomic testing into the clinical research arsenal will greatly facilitate our understanding of the epigenetic basis of disease and help identify novel therapeutic targets. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Stoccoro, Andrea; Karlsson, Hanna L; Coppedè, Fabio; Migliore, Lucia
The term epigenetics includes several phenomena such as DNA methylation, histone tail modifications, and microRNA mediated mechanisms, which are able to mold the chromatin structure and/or gene expression levels, without altering the primary DNA sequence. Environmental agents can exert epigenetic properties and there is increasing evidence of epigenetic deregulation of gene expression in several human diseases, including cancer, cardiovascular diseases, autism spectrum disorders, autoimmune diseases, and neurodegeneration, among others. Given the widespread use and dispersion in the environment of nano-sized materials, this article summarizes the studies performed so far to evaluate their potential epigenetic properties. Those studies highlight the ability of certain nano-sized compounds to induce an impaired expression of genes involved in DNA methylation reactions leading to global DNA methylation changes, as well as changes of gene specific methylation of tumor suppressor genes, inflammatory genes, and DNA repair genes, all potentially involved in cancer development. Moreover, some nano-sized compounds are able to induce changes in the acetylation and methylation of histone tails, as well as microRNA deregulated expression. We also provided a detailed description of currently available methodologies to evaluate epigenetic modifications. Standard protocols are currently available to evaluate cytotoxic and genotoxic effects of nano-sized materials. By contrast, there are at present no available standard protocols to evaluate the epigenetic potential of any given compound. The currently available methodologies offer different, but often complementary information to characterize potential epigenetic changes induced by exposure to nano-sized compounds. Given the widespread use and dispersion in the environment of nano-sized materials, at present and foreseeable in the near future, and in light of the indication of potential epigenetic properties here reviewed, more
Cazaly, Emma; Charlesworth, Jac; Dickinson, Joanne L; Holloway, Adele F
The field of epigenetics and our understanding of the mechanisms that regulate the establishment, maintenance and heritability of epigenetic patterns continue to grow at a remarkable rate. This information is providing increased understanding of the role of epigenetic changes in disease, insight into the underlying causes of these epigenetic changes and revealing new avenues for therapeutic intervention. Epigenetic modifiers are increasingly being pursued as therapeutic targets in a range of diseases, with a number of agents targeting epigenetic modifications already proving effective in diseases such as cancer. Although it is well established that DNA mutations and aberrant expression of epigenetic modifiers play a key role in disease, attention is now turning to the interplay between genetic and epigenetic factors in complex disease etiology. The role of genetic variability in determining epigenetic profiles, which can then be modified by environmental and stochastic factors, is becoming more apparent. Understanding the interplay between genetic and epigenetic factors is likely to aid in identifying individuals most likely to benefit from epigenetic therapies. This goal is coming closer to realization because of continual advances in laboratory and statistical tools enabling improvements in the integration of genomic, epigenomic and phenotypic data.
Alabert, Constance; Groth, Anja
initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA...
Alabert, Constance; Jasencakova, Zuzana; Groth, Anja
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...
Full Text Available Background: Cancer development is not restricted to the genetic changes, but also to epigenetic changes. Epigenetic processes are very important in the development of hematological malignancies. The main epigenetic alterations are aberrations in DNA methylation, post-translational modifications of histones, chromatin remodeling and microRNAs patterns, and these are associated with tumor genesis. All the various cellular pathways contributing to the neoplastic phenotype are affected by epigenetic genes in cancer. These pathways can be explored as biomarkers in clinical use for early detection of disease, malignancy classification and response to treatment with classical chemotherapy agents and epigenetic drugs. Materials and Method: A literature review was performed using PUBMED from 1985 to 2008. Cross referencing of discovered articles was also reviewed.Results: In chronic lymphocytic leukemia, regional hypermethylation of gene promoters leads to gene silencing. Many of these genes have tumor suppressor phenotypes. In myelodysplastic syndrome (MDS, CDKN2B (alias, P15, a cyclin-dependent kinase inhibitor that negatively regulates the cell cycle, has been shown to be hypermethylated in marrow stem (CD34+ cells in patients with MDS. At present both Vidaza and Decitabine (DNA methyltransferase inhibitors are approved for the treatment of MDS.Conclusion: Unlike mutations or deletions, DNA hypermethylation and histone deacetylation are potentially reversible by pharmacological inhibition, therefore those epigenetic changes have been recognized as promising novel therapeutic targets in hematopoietic malignances. In this review, we discussed molecular mechanisms of epigenetics, epigenetic changes in hematological malignancies and epigenetic based treatments
Miranda, Tina B; Voss, Ty C; Sung, Myong-Hee
, mechanistic details defining the cellular interactions between ER and GR are poorly understood. We investigated genome-wide binding profiles for ER and GR upon coactivation and characterized the status of the chromatin landscape. We describe a novel mechanism dictating the molecular interplay between ER...
Terms to be familiar with before you start to solve the test: chromatin, nucleases, sucrose density gradient centrifugation, melting point, gel electrophoresis, ethidium bromide, autoradiography, Southern blotting, Northern blotting, Sanger sequencing, restriction endonucleases, exonucleases, linker DNA, chloroform extraction, nucleosomes,…
Pecinka, Ales; Abdelsamad, Ahmed; Vu, Giang T H
Transcriptional gene silencing (TGS) is an epigenetic mechanism that suppresses the activity of repetitive DNA elements via accumulation of repressive chromatin marks. We discuss natural variation in TGS, with a particular focus on cases that affect the function of protein-coding genes and lead to developmental or physiological changes. Comparison of the examples described has revealed that most natural variation is associated with genetic determinants, such as gene rearrangements, inverted repeats, and transposon insertions that triggered TGS. Recent technical advances have enabled the study of epigenetic natural variation at a whole-genome scale and revealed patterns of inter- and intraspecific epigenetic variation. Future studies exploring non-model species may reveal species-specific evolutionary adaptations at the level of chromatin configuration. Copyright © 2013 Elsevier Ltd. All rights reserved.
Lalmansingh, Avin S; Karmakar, Sudipan; Jin, Yetao; Nagaich, Akhilesh K
Forkhead box (FOX) proteins represent a large family of transcriptional regulators unified by their DNA binding domain (DBD) known as a 'forkhead' or 'winged helix' domain. Over 40 FOX genes have been identified in the mammalian genome. FOX proteins share significant sequence similarities in the DBD which allow them to bind to a consensus DNA response element. However, their modes of action are quite diverse as they regulate gene expression by acting as pioneer factors, transcription factors, or both. This review focuses on the mechanisms of chromatin remodeling with an emphasis on three sub-classes-FOXA, FOXO, and FOXP members. FOXA proteins serve as pioneer factors to open up local chromatin structure and thereby increase accessibility of chromatin to factors regulating transcription. FOXP proteins, in contrast, function as classic transcription factors to recruit a variety of chromatin modifying enzymes to regulate gene expression. FOXO proteins represent a hybrid subclass having dual roles as pioneering factors and transcription factors. A subset of FOX proteins interacts with condensed mitotic chromatin and may function as 'bookmarking' agents to maintain transcriptional competence at specific genomic sites. The overall diversity in chromatin remodeling function by FOX proteins is related to unique structural motifs present within the DBD flanking regions that govern selective interactions with core histones and/or chromatin coregulatory proteins. This article is part of a Special Issue entitled: Chromatin in time and space. Published by Elsevier B.V.
Lenstra, Tineke L; Holstege, Frank C P
The influence of chromatin on many cellular processes is well appreciated. Much has been learned by studying the role of chromatin remodeling and modifying complexes on individual genes. The seemingly straightforward models that inevitably arise from such studies are challenged by genome-wide analyses. Two recent studies in Saccharomyces cerevisiae provide unprecedented coverage of both the genome-wide location and the effect on gene expression for the majority of chromatin factors. Comparison of the overlap between location and expression effects reveals a large disconnect, with on average only 2.5% of occupied genes showing changes in expression. It is also interesting that only 24% of all expression effects are associated with chromatin factor occupancy. The large difference between location and effect likely reflects general properties inherent to regulation of gene expression through chromatin in yeast. Explanations for the discrepancy include gene-specific properties that exert a requirement for certain factors only on specific genes, as well as functional redundancy, whereby loss of a particular factor is compensated by others that function in a distinct but nevertheless compensatory manner. Since the majority of chromatin factor perturbations do show significant effects on specific subsets of genes, this implies the presence of different types of gene-specific properties that determine which chromatin factors a particular gene requires for proper expression. Understanding these gene-specific properties should be the focus of future studies aimed at understanding regulation of gene expression through chromatin.
Epigenetics refers to the study of heritable changes in gene expression not involving changes in DNA sequence and is presently an active area of research in biology and medicine. There is increasing evidence that epigenetics is involved in the pathogenesis of psychiatric disorders. Several studies conducted to date have suggested that psychosocial factors act by modifying epigenetic mechanisms of gene expression in the brain in the pathogenesis of psychiatric disorders. Such studies have been conducted both on brain tissues and also using peripheral tissues as substitutes for brain tissues. This article reviews such studies. Epigenetic mechanisms of gene expression in the brain appear to link one individual with another in the context of social psychiatry. Epigenetics appears to be of major importance to the field of social psychiatry.
Roh, Tae-Young; Zhao, Keji
One major postgenomic challenge is to characterize the epigenomes that control genome functions. The epigenomes are mainly defined by the specific association of nonhistone proteins with chromatin and the covalent modifications of chromatin, including DNA methylation and posttranslational histone modifications. The in vivo protein-binding and chromatin-modification patterns can be revealed by the chromatin immunoprecipitation assay (ChIP). By combining the ChIP assays and the serial analysis of gene expression (SAGE) protocols, we have developed an unbiased and high-resolution genome-wide mapping technique (GMAT) to determine the genome-wide protein-targeting and chromatin-modification patterns. GMAT has been successfully applied to mapping the target sites of the histone acetyltransferase, Gcn5p, in yeast and to the discovery of the histone acetylation islands as an epigenetic mark for functional regulatory elements in the human genome.
Jakub, James W; Grotz, Travis E; Jordan, Philip; Hunter, Ewan; Pittelkow, Mark; Ramadass, Aroul; Akoulitchev, Alexandre; Markovic, Svetomir
Prognosis is markedly improved when melanoma is diagnosed early. Improved methods are needed for earlier detection and screening. We hypothesized that epigenetic analysis of blood samples could discriminate patients with melanoma from patients with other cutaneous lesions and from healthy volunteers. After institutional review board approval and consent, whole blood was obtained from 59 patients with melanoma, 20 patients with other skin cancers, 20 patients with benign skin conditions, and 20 healthy volunteers. Fifteen conformation biomarkers from five gene loci were analyzed on chromatin with the EpiSwitch technology using a modified chromatin conformation capture assay. Differentiation between patients with melanoma and those with nonmelanoma skin cancers was correct 85% of the time, resulting in a sensitivity of 88% and a specificity of 82%. Differentiation of patients with melanoma from healthy controls was correct 80% of the time, resulting in a sensitivity of 85% and a specificity of 75%. The noninvasive test was more accurate in early-stage melanoma (1/10 and 1/16 stage I and stage II patients were misclassified, respectively) and became less accurate with more advanced disease (3/14 and 4/19 stage III and IV patients were misclassified, respectively). We report the results of a noninvasive test using chromosomal aberrations and epigenetic changes identified in peripheral blood that, in this pilot study, distinguished patients with early-stage melanoma from other cohorts.
Lo, Albert; Qi, Lei
The discovery and adaption of bacterial clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) systems has revolutionized the way researchers edit genomes. Engineering of catalytically inactivated Cas variants (nuclease-deficient or nuclease-deactivated [dCas]) combined with transcriptional repressors, activators, or epigenetic modifiers enable sequence-specific regulation of gene expression and chromatin state. These CRISPR–Cas-based technologies have contributed to the rapid development of disease models and functional genomics screening approaches, which can facilitate genetic target identification and drug discovery. In this short review, we will cover recent advances of CRISPR–dCas9 systems and their use for transcriptional repression and activation, epigenome editing, and engineered synthetic circuits for complex control of the mammalian genome. PMID:28649363
Full Text Available Non-coding RNAs (ncRNAs are regulatory elements of gene expression and chromatin structure. Both long and small ncRNAs can also act as inductors and targets of epigenetic programs. Epigenetic patterns can be transmitted from one cell to the daughter cell, but, importantly, also through generations. Diversity of ncRNAs is emerging with new and surprising roles. Functional interactions among ncRNAs and between specific ncRNAs and structural elements of the chromatin are drawing a complex landscape. In this scenario, epigenetic changes induced by environmental stressors, including reprotoxicants, can explain some transgenerationally-transmitted phenotypes in non-Mendelian ways. In this review, we analyze mechanisms of action of reprotoxicants upon different types of ncRNAs and epigenetic modifications causing transgenerationally transmitted characters through germ cells but affecting germ cells and reproductive systems. A functional model of epigenetic mechanisms of transgenerational transmission ncRNAs-mediated is also proposed.
José Fernando Maya-Vetencourt
Full Text Available Neuronal circuitries in the mammalian visual system change as a function of experience. Sensory experience modifies neuronal networks connectivity via the activation of different physiological processes such as excitatory/inhibitory synaptic transmission, neurotrophins, and signaling of extracellular matrix molecules. Long-lasting phenomena of plasticity occur when intracellular signal transduction pathways promote epigenetic alterations of chromatin structure that regulate the induction of transcription factors that in turn drive the expression of downstream targets, the products of which then work via the activation of structural and functional mechanisms that modify synaptic connectivity. Here, we review recent findings in the field of visual cortical plasticity while focusing on how physiological mechanisms associated with experience promote structural changes that determine functional modifications of neural circuitries in V1. We revise the role of microRNAs as molecular transducers of environmental stimuli and the role of immediate early genes that control gene expression programs underlying plasticity in the developing visual cortex.
Full Text Available Background: The regenerative capacity of the mammalian heart is quite limited. Recent reports have focused on reprogramming mesenchymal stem cells into cardiomyocytes. We investigated whether fibroblasts could transdifferentiate into myocardium. Methods: Mouse embryonic fibroblasts were treated with Trichostatin A (TSA and 5-Aza-2-Deoxycytidine (5-aza-dC. The treated cells were permeabilized with streptolysin O and exposed to the mouse cardiomyocyte extract and cultured for 1, 10, and 21 days. Cardiomyocyte markers were detected by immunohistochemistry. Alkaline phosphatase activity and OCT4 were also detected in cells treated by chromatin-modifying agents. Results: The cells exposed to a combination of 5-aza-dC and TSA and permeabilized in the presence of the cardiomyocyte extract showed morphological changes. The cells were unable to express cardiomyocyte markers after 24 h. Immunocytochemical assays showed a notable degree of myosin heavy chain and α-actinin expressions after 10 days. The expression of the natriuretic factor and troponin T occurred after 21 days in these cells. The cells exposed to chromatin-modifying agents also expressed cardiomyocyte markers; however, the proportion of reprogrammed cells was clearly smaller than that in the cultures exposed to 5-aza-dC , TSA, and extract. Conclusion: It seems that the fibroblasts were able to eliminate the previous epigenetic markers and form new ones according to the factors existing in the extract. Since no beating was observed, at least up to 21 days, the cells may need an appropriate extracellular matrix for their function.
Fransz, P.; Meier, I.
The inheritance of biological traits involves not only the transfer of genetic information in the form of DNA, but also epigenetic information. The latter is encrypted in a DNA component, methylation of cytosine residues, and in non-DNA components such as histone modifications, non-histone proteins,
Fortress, Ashley M.; Frick, Karyn M.
Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. PMID:24878494
Full Text Available Abstract Background The micropropagation is a powerful tool to scale up plants of economical and agronomical importance, enhancing crop productivity. However, a small but growing body of evidence suggests that epigenetic mechanisms, such as DNA methylation and histone modifications, can be affected under the in vitro conditions characteristic of micropropagation. Here, we tested whether the adaptation to different in vitro systems (Magenta boxes and Bioreactors modified epigenetically different clones of Agave fourcroydes and A. angustifolia. Furthermore, we assessed whether these epigenetic changes affect the regulatory expression of KNOTTED1-like HOMEOBOX (KNOX transcription factors. Results To gain a better understanding of epigenetic changes during in vitro and ex vitro conditions in Agave fourcroydes and A. angustifolia, we analyzed global DNA methylation, as well as different histone modification marks, in two different systems: semisolid in Magenta boxes (M and temporary immersion in modular Bioreactors (B. No significant difference was found in DNA methylation in A. fourcroydes grown in either M or B. However, when A. fourcroydes was compared with A. angustifolia, there was a two-fold difference in DNA methylation between the species, independent of the in vitro system used. Furthermore, we detected an absence or a low amount of the repressive mark H3K9me2 in ex vitro conditions in plants that were cultured earlier either in M or B. Moreover, the expression of AtqKNOX1 and AtqKNOX2, on A. fourcroydes and A. angustifolia clones, is affected during in vitro conditions. Therefore, we used Chromatin ImmunoPrecipitation (ChIP to know whether these genes were epigenetically regulated. In the case of AtqKNOX1, the H3K4me3 and H3K9me2 were affected during in vitro conditions in comparison with AtqKNOX2. Conclusions Agave clones plants with higher DNA methylation during in vitro conditions were better adapted to ex vitro conditions. In addition
Full Text Available The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.
Fiziev, Petko; Akdemir, Kadir C; Miller, John P; Keung, Emily Z; Samant, Neha S; Sharma, Sneha; Natale, Christopher A; Terranova, Christopher J; Maitituoheti, Mayinuer; Amin, Samirkumar B; Martinez-Ledesma, Emmanuel; Dhamdhere, Mayura; Axelrad, Jacob B; Shah, Amiksha; Cheng, Christine S; Mahadeshwar, Harshad; Seth, Sahil; Barton, Michelle C; Protopopov, Alexei; Tsai, Kenneth Y; Davies, Michael A; Garcia, Benjamin A; Amit, Ido; Chin, Lynda; Ernst, Jason; Rai, Kunal
The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Puckett, Rosemary E; Lubin, Farah D
Epigenetic mechanisms have long been associated with the regulation of gene-expression changes accompanying normal neuronal development and cellular differentiation; however, until recently these mechanisms were believed to be statically quiet in the adult brain. Behavioral neuroscientists have now begun to investigate these epigenetic mechanisms as potential regulators of gene-transcription changes in the CNS subserving synaptic plasticity and long-term memory (LTM) formation. Experimental evidence from learning and memory animal models has demonstrated that active chromatin remodeling occurs in terminally differentiated postmitotic neurons, suggesting that these molecular processes are indeed intimately involved in several stages of LTM formation, including consolidation, reconsolidation and extinction. Such chromatin modifications include the phosphorylation, acetylation and methylation of histone proteins and the methylation of associated DNA to subsequently affect transcriptional gene readout triggered by learning. The present article examines how such learning-induced epigenetic changes contribute to LTM formation and influence behavior. In particular, this article is a survey of the specific epigenetic mechanisms that have been demonstrated to regulate gene expression for both transcription factors and growth factors in the CNS, which are critical for LTM formation and storage, as well as how aberrant epigenetic processing can contribute to psychological states such as schizophrenia and drug addiction. Together, the findings highlighted in this article support a novel role for epigenetic mechanisms in the adult CNS serving as potential key molecular regulators of gene-transcription changes necessary for LTM formation and adult behavior. PMID:22126252
Iglesias, Francisco M; Cerdán, Pablo D
Biotic and abiotic stresses alter the pattern of gene expression in plants. Depending on the frequency and duration of stress events, the effects on the transcriptional state of genes are "remembered" temporally or transmitted to daughter cells and, in some instances, even to offspring (transgenerational epigenetic inheritance). This "memory" effect, which can be found even in the absence of the original stress, has an epigenetic basis, through molecular mechanisms that take place at the chromatin and DNA level but do not imply changes in the DNA sequence. Many epigenetic mechanisms have been described and involve covalent modifications on the DNA and histones, such as DNA methylation, histone acetylation and methylation, and RNAi dependent silencing mechanisms. Some of these chromatin modifications need to be stable through cell division in order to be truly epigenetic. During DNA replication, histones are recycled during the formation of the new nucleosomes and this process is tightly regulated. Perturbations to the DNA replication process and/or the recycling of histones lead to epigenetic changes. In this mini-review, we discuss recent evidence aimed at linking DNA replication process to epigenetic inheritance in plants.
Shukla, Samriddhi; Meeran, Syed M; Katiyar, Santosh K
The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Full Text Available Biotic and abiotic stresses alter the pattern of gene expression in plants. Depending on the frequency and duration of stress events, the effects on the transcriptional state of genes are remembered temporally or transmitted to daughter cells and, in some instances, even to offspring (transgenerational epigenetic inheritance. This memory effect, which can be found even in the absence of the original stress, has an epigenetic basis, through molecular mechanisms that take place at the chromatin and DNA level but do not imply changes in the DNA sequence. Many epigenetic mechanisms have been described and involve covalent modifications on the DNA and histones, such as DNA methylation, histone acetylation and methylation, and RNAi dependent silencing mechanisms. Some of these chromatin modifications need to be stable through cell division in order to be truly epigenetic. During DNA replication, histones are recycled during the formation of the new nucleosomes and this process is tightly regulated. Perturbations to the DNA replication process and/or the recycling of histones lead to epigenetic changes. In this mini-review, we discuss recent evidence aimed at linking DNA replication process to epigenetic inheritance in plants.
Puckett, Rosemary E; Lubin, Farah D
Epigenetic mechanisms have long been associated with the regulation of gene-expression changes accompanying normal neuronal development and cellular differentiation; however, until recently these mechanisms were believed to be statically quiet in the adult brain. Behavioral neuroscientists have now begun to investigate these epigenetic mechanisms as potential regulators of gene-transcription changes in the CNS subserving synaptic plasticity and long-term memory (LTM) formation. Experimental evidence from learning and memory animal models has demonstrated that active chromatin remodeling occurs in terminally differentiated postmitotic neurons, suggesting that these molecular processes are indeed intimately involved in several stages of LTM formation, including consolidation, reconsolidation and extinction. Such chromatin modifications include the phosphorylation, acetylation and methylation of histone proteins and the methylation of associated DNA to subsequently affect transcriptional gene readout triggered by learning. The present article examines how such learning-induced epigenetic changes contribute to LTM formation and influence behavior. In particular, this article is a survey of the specific epigenetic mechanisms that have been demonstrated to regulate gene expression for both transcription factors and growth factors in the CNS, which are critical for LTM formation and storage, as well as how aberrant epigenetic processing can contribute to psychological states such as schizophrenia and drug addiction. Together, the findings highlighted in this article support a novel role for epigenetic mechanisms in the adult CNS serving as potential key molecular regulators of gene-transcription changes necessary for LTM formation and adult behavior.
Carson, William F; Cavassani, Karen A; Soares, Elyara M; Hirai, Soichiro; Kittan, Nicolai A; Schaller, Matthew A; Scola, Melissa M; Joshi, Amrita; Matsukawa, Akihiro; Aronoff, David M; Johnson, Craig N; Dou, Yali; Gallagher, Katherine A; Kunkel, Steven L
Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function have been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-κB. Therefore, we sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre(+/-) MLL1(fx/fx)) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1-knockout macrophages identified numerous genes involved with inflammatory responses whose expression was altered in response to TLR ligands or proinflammatory cytokines, including STAT4. STAT4-dependent cytokines, such as type I IFNs were able to drive MLL1 expression in macrophages, and MLL1-knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions. Copyright © 2017 by The American Association of Immunologists, Inc.
Cordero, Paul; Li, Jiawei; Oben, Jude A
After the study of the gene code as a trigger for obesity, epigenetic code has appeared as a novel tool in the diagnosis, prognosis and treatment of obesity, and its related comorbidities. This review summarizes the status of the epigenetic field associated with obesity, and the current epigenetic-based approaches for obesity treatment. Thanks to technical advances, novel and key obesity-associated polymorphisms have been described by genome-wide association studies, but there are limitations with their predictive power. Epigenetics is also studied for disease association, which involves decoding of the genome information, transcriptional status and later phenotypes. Obesity could be induced during adult life by feeding and other environmental factors, and there is a strong association between obesity features and specific epigenetic patterns. These patterns could be established during early life stages, and programme the risk of obesity and its comorbidities during adult life. Furthermore, recent studies have shown that DNA methylation profile could be applied as biomarkers of diet-induced weight loss treatment. High-throughput technologies, recently implemented for commercial genetic test panels, could soon lead to the creation of epigenetic test panels for obesity. Nonetheless, epigenetics is a modifiable risk factor, and different dietary patterns or environmental insights during distinct stages of life could lead to rewriting of the epigenetic profile.
Ledón-Rettig, Cris C
Phenotypic variation arises from interactions between environmental and genetic variation, and the emergence of such variation is, in part, mediated by epigenetic mechanisms: factors that modify gene expression but do not change the gene sequence, per se. The role of epigenetic variation and inheritance in natural populations, however, remains poorly understood. The budding field of Ecological Epigenetics seeks to extend our knowledge of epigenetic mechanisms and processes to natural populations, and recent conceptual and technical advances have made progress toward this goal more feasible. In light of these breakthroughs, now is a particularly opportune time to develop a framework that will guide and facilitate exceptional studies in Ecological Epigenetics. Toward this goal, the Ecological Epigenetics symposium brought together researchers with diverse strengths in theory, developmental genetics, ecology, and evolution, and the proceedings from their talks are presented in this issue. By characterizing environmentally dependent epigenetic variation in natural populations, we will enhance our understanding of developmental, ecological, and evolutionary phenomena. In particular, ecological epigenetics has the potential to explain how populations endure (or fail to endure) profound and rapid environmental change. Here, my goal is to introduce some of the common goals and challenges shared by those pursuing this critical field.
Feng, Suhua; Jacobsen, Steven E
Plant genomes are modified by an array of epigenetic marks that help regulate plant growth and reproduction. Although plants share many epigenetic features with animals and fungi, some epigenetic marks are unique to plants. In different organisms, the same epigenetic mark can play different roles and/or similar functions can be carried out by different epigenetic marks. Furthermore, while the enzymatic systems responsible for generating or eliminating epigenetic marks are often conserved, there are also cases where they are quite divergent between plants and other organisms. DNA methylation and methylation of histone tails on the lysine 4, 9, and 27 positions are among the best characterized epigenetic marks in both plants and animals. Recent studies have greatly enhanced our knowledge about the pattern of these marks in various genomes and provided insights into how they are established and maintained and how they function. This review focuses on the conservation and divergence of the pathways that mediate these four types of epigenetic marks. Copyright © 2010 Elsevier Ltd. All rights reserved.
Rasmussen, Morten; Zierath, Juleen R; Barrès, Romain
Skeletal muscle is a malleable organ that responds to a single acute exercise bout by inducing the expression of genes involved in structural, metabolic and functional adaptations. Several epigenetic mechanisms including histone H4 deacetylation and loss of promoter methylation have been implicated...... in modifying exercise-responsive gene expression. These transient changes suggest that epigenetic mechanisms are not restricted to early stages of human development but are broad dynamic controllers of genomic plasticity in response to environmental factors....
Full Text Available Coronaviruses (CoV comprise a large group of emerging human and animal pathogens, including the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV strains. The molecular mechanisms regulating emerging coronavirus pathogenesis are complex and include virus–host interactions associated with entry, replication, egress and innate immune control. Epigenetics research investigates the genetic and non-genetic factors that regulate phenotypic variation, usually caused by external and environmental factors that alter host expression patterns and performance without any change in the underlying genotype. Epigenetic modifications, such as histone modifications, DNA methylation, chromatin remodeling, and non-coding RNAs, function as important regulators that remodel host chromatin, altering host expression patterns and networks in a highly flexible manner. For most of the past two and a half decades, research has focused on the molecular mechanisms by which RNA viruses antagonize the signaling and sensing components that regulate induction of the host innate immune and antiviral defense programs upon infection. More recently, a growing body of evidence supports the hypothesis that viruses, even lytic RNA viruses that replicate in the cytoplasm, have developed intricate, highly evolved, and well-coordinated processes that are designed to regulate the host epigenome, and control host innate immune antiviral defense processes, thereby promoting robust virus replication and pathogenesis. In this article, we discuss the strategies that are used to evaluate the mechanisms by which viruses regulate the host epigenome, especially focusing on highly pathogenic respiratory RNA virus infections as a model. By combining measures of epigenome reorganization with RNA and proteomic datasets, we articulate a spatial-temporal data integration approach to identify regulatory genomic clusters
Ourania M. Andrisani
Full Text Available This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain ‘cellular memory’ by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs, likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2 mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3. Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1, the activating trimethylation of H3 on lysine-4 (H3K4me3. Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell.
Andrisani, Ourania M
This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain 'cellular memory' by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs), likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2) mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3). Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1), the activating trimethylation of H3 on lysine-4 (H3K4me3). Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell.
Buckley, Noel J; Johnson, Rory; Zuccato, Chiara; Bithell, Angela; Cattaneo, Elena
Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD. (c) 2010 Elsevier Inc. All rights reserved.
Alló, M; Schor, I E; Muñoz, M J; de la Mata, M; Agirre, E; Valcárcel, J; Eyras, E; Kornblihtt, A R
Alternative splicing affects more than 90% of human genes. Coupling between transcription and splicing has become crucial in the complex network underlying alternative splicing regulation. Because chromatin is the real template for nuclear transcription, changes in its structure, but also in the "reading" and "writing" of the histone code, could modulate splicing choices. Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons. We focus on two recent reports from our laboratories that add new evidence to this field. The first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene. In the second report, we show how specific histone modifications can be created at targeted gene regions as a way to affect alternative splicing: Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNA-mediated transcriptional gene silencing.
Dikovskaya, Dina; Khoudoli, Guennadi; Newton, Ian P.; Chadha, Gaganmeet S.; Klotz, Daniel; Visvanathan, Ashwat; Lamond, Angus; Swedlow, Jason R.; Näthke, Inke S.
The tumour suppressor Adenomatous Polyposis Coli (APC) is required for proper mitosis; however, the exact role of APC in mitosis is not understood. Using demembranated sperm chromatin exposed to meiotic Xenopus egg extract and HeLa cells expressing fluorescently labelled histones, we established that APC contributes to chromatin compaction. Sperm chromatin in APC-depleted Xenopus egg extract frequently formed tight round or elongated structures. Such abnormally compacted chromatin predominantly formed spindles with low microtubule content. Furthermore, in mitotic HeLa cells expressing GFP- and mCherry-labelled H2B histones, depletion of APC caused a decrease in the donor fluorescence lifetime of neighbouring fluorophores, indicative of excessive chromatin compaction. Profiling the chromatin-associated proteome of sperm chromatin incubated with Xenopus egg extracts revealed temporal APC-dependent changes in the abundance of histones, closely mirrored by chromatin-associated Topoisomerase IIa, condensin I complex and Kif4. In the absence of APC these factors initially accumulated on chromatin, but then decreased faster than in controls. We also found and validated significant APC-dependent changes in chromatin modifiers Set-a and Rbbp7. Both were decreased on chromatin in APC-depleted extract; in addition, the kinetics of association of Set-a with chromatin was altered in the absence of APC. PMID:22719865
Ordovás, José M; Smith, Caren E
Despite advances in the prevention and management of cardiovascular disease (CVD), this group of multifactorial disorders remains a leading cause of mortality worldwide. CVD is associated with multiple genetic and modifiable risk factors; however, known environmental and genetic influences can only explain a small part of the variability in CVD risk, which is a major obstacle for its prevention and treatment. A more thorough understanding of the factors that contribute to CVD is, therefore, needed to develop more efficacious and cost-effective therapy. Application of the 'omics' technologies will hopefully make these advances a reality. Epigenomics has emerged as one of the most promising areas that will address some of the gaps in our current knowledge of the interaction between nature and nurture in the development of CVD. Epigenetic mechanisms include DNA methylation, histone modification, and microRNA alterations, which collectively enable the cell to respond quickly to environmental changes. A number of CVD risk factors, such as nutrition, smoking, pollution, stress, and the circadian rhythm, have been associated with modification of epigenetic marks. Further examination of these mechanisms may lead to earlier prevention and novel therapy for CVD.
Full Text Available The ability to maintain quiescence is critical for the long-term maintenance of a functional stem cell pool. To date, the epigenetic and transcriptional characteristics of quiescent stem cells and how they change with age remain largely unknown. In this study, we explore the chromatin features of adult skeletal muscle stem cells, or satellite cells (SCs, which reside predominantly in a quiescent state in fully developed limb muscles of both young and aged mice. Using a ChIP-seq approach to obtain global epigenetic profiles of quiescent SCs (QSCs, we show that QSCs possess a permissive chromatin state in which few genes are epigenetically repressed by Polycomb group (PcG-mediated histone 3 lysine 27 trimethylation (H3K27me3, and a large number of genes encoding regulators that specify nonmyogenic lineages are demarcated by bivalent domains at their transcription start sites (TSSs. By comparing epigenetic profiles of QSCs from young and old mice, we also provide direct evidence that, with age, epigenetic changes accumulate and may lead to a functional decline in quiescent stem cells. These findings highlight the importance of chromatin mapping in understanding unique features of stem cell identity and stem cell aging.
LaPlant, Quincey; Nestler, Eric J
Epigenetics, the nongenetic component of how chromatin structure influences gene expression, is amazingly complex, and linking how environmental stimuli can influence epigenetic 'gene programs' in specific nerve cells to ultimately control behavior is a seemingly insurmountable puzzle. Cocaine is a highly potent stimulus capable of influencing behavior for the lifetime of an organism. Not surprisingly, psychostimulant-induced epigenetic regulation of gene expression has thus been identified as key to understanding the pathology of addiction. In addition to identifying this essential role of epigenetics in addiction, several important concepts have emerged such as the importance of global, temporal, and spatial control of mRNA expression in considering any given histone modification's influence on a given gene. Adding to this complexity, one has to account for the cumulative influence of other epigenetic modifications on a gene's transcription in addition to the interplay between transcription factors and chromatin structure. This review highlights how bioinformatic, molecular, and behavioral studies on addiction provide new insight into these concepts and outlines two distinct psychostimulant-induced patterns of chromatin regulation which are thought to underlie unique programs of gene expression that contribute importantly to the addicted state. Published by Elsevier Inc.
The term epigenetics was coined in 1942 by C.H. Waddington in the context of studies on development. Since then, the meaning of epigenetics changed over time. In the beginning, epigenetics was viewed as a phenomenon above and beyond genetics. Epigenetic explanations were invoked when genetics could not explain a phenomenon. From the mid-seventies, the state of understanding started changing. Epigenetics has now morphed from a phenomenon to a branch of science whose molecular underpinnings are well understood. The current state of knowledge of epigenetics has evolved as our understanding of DNA methylation, chromatin modifications, and noncoding RNA, and their effects on gene expression increased. At this time in the annals of epigentics research, it is appropriate to revisit some of the important discoveries that have helped advance the field to its current state. This is a very brief review of some early discoveries, and by no means is a complete account of the history of epigenetics. In this review, the early history has also been emphasized in order to underscore the transformation of the science of epigenetics from a phenomenon to a modern field of intense research.
Sui, Xinbing; Zhu, Jing; Zhou, Jichun; Wang, Xian; Li, Da; Han, Weidong; Fang, Yong; Pan, Hongming
Epigenetic modifications have been considered as hallmarks of cancer and play an important role in tumor initiation and development. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, may regulate cell cycle and apoptosis, as well as macroautophagy (hereafter referred to as autophagy). Autophagy, as a crucial cellular homeostatic mechanism, performs a dual role, having pro-survival or pro-death properties. A variety of signaling pathways including epigenetic control have been implicated in the upregulation or downregulation of autophagy. However, the role of epigenetic regulation in autophagy is still less well acknowledged. Recent studies have linked epigenetic control to the autophagic process. Some epigenetic modifiers are also involved in the regulation of autophagy and potentiate the efficacy of traditional therapeutics. Thus, understanding the novel functions of epigenetic control in autophagy may allow us to develop potential therapeutic approaches for cancer treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Uppal, Timsy [Department of Microbiology and Immunology, School of Medicine, University of Nevada, 1664 N Virginia Street, MS 320, Reno, NV 89557 (United States); Jha, Hem C. [Department of Microbiology and the Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104 (United States); Verma, Subhash C. [Department of Microbiology and Immunology, School of Medicine, University of Nevada, 1664 N Virginia Street, MS 320, Reno, NV 89557 (United States); Robertson, Erle S., E-mail: email@example.com [Department of Microbiology and the Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104 (United States)
Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes is tightly regulated by both the viral and cellular factors. Recent advancements in identifying the expression profiles of viral transcripts, using tilling arrays and next generation sequencing have identified additional coding and non-coding transcripts in the KSHV genome. Determining the functions of these transcripts will provide a better understanding of the mechanisms utilized by KSHV in altering cellular pathways involved in promoting cell growth and tumorigenesis. Replication of the viral genome is critical in maintaining the existing copies of the viral episomes during both latent and lytic phases of the viral life cycle. The replication of the viral episome is facilitated by viral components responsible for recruiting chromatin modifying enzymes and replication factors for altering the chromatin complexity and replication initiation functions, respectively. Importantly, chromatin modification of the viral genome plays a crucial role in determining whether the viral genome will persist as latent episome or undergo lytic reactivation. Additionally, chromatinization of the incoming virion DNA, which lacks chromatin structure, in the target cells during primary infection, helps in establishing latent infection. Here, we discuss the recent advancements on our understating of KSHV genome chromatinization and the consequences of chromatin modifications on viral life cycle.
Full Text Available Kaposi’s sarcoma-associated herpesvirus (KSHV belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes is tightly regulated by both the viral and cellular factors. Recent advancements in identifying the expression profiles of viral transcripts, using tilling arrays and next generation sequencing have identified additional coding and non-coding transcripts in the KSHV genome. Determining the functions of these transcripts will provide a better understanding of the mechanisms utilized by KSHV in altering cellular pathways involved in promoting cell growth and tumorigenesis. Replication of the viral genome is critical in maintaining the existing copies of the viral episomes during both latent and lytic phases of the viral life cycle. The replication of the viral episome is facilitated by viral components responsible for recruiting chromatin modifying enzymes and replication factors for altering the chromatin complexity and replication initiation functions, respectively. Importantly, chromatin modification of the viral genome plays a crucial role in determining whether the viral genome will persist as latent episome or undergo lytic reactivation. Additionally, chromatinization of the incoming virion DNA, which lacks chromatin structure, in the target cells during primary infection, helps in establishing latent infection. Here, we discuss the recent advancements on our understating of KSHV genome chromatinization and the consequences of chromatin modifications on viral life cycle.
Kasinska, Marta A; Drzewoski, Jozef; Sliwinska, Agnieszka
The growing number of people suffering from obesity and type 2 diabetes mellitus (T2DM) is a global health problem that results in increased mortality from their complications, mainly cardiovascular diseases. Although the relationship between obesity and T2DM is well established, the common molecular pathomechanisms are still under investigation. Recently, it has been suggested that epigenetic modifications may be involved in both obesity and T2DM development. Epigenetics plays a pivotal role in the regulation of gene expression by the reversible modifications of chromatin structure without any changes in DNA sequence. Epigenetic modifications include DNA methylation, posttranslational histone modifications and miRNA interference. Therefore, the aim of this article is to discuss the current knowledge on epigenetic modifications in adipose tissue and their association with obesity and T2DM.
Stefano ede Pretis
Full Text Available A multi-layered set of epigenetic marks, including post-translational modifications of histones and methylation of DNA, is finely tuned to define the epigenetic state of chromatin in any given cell type under specific conditions. Recently, the knowledge about the combinations of epigenetic marks occurring in the genome of different cell types under various conditions is rapidly increasing. Computational methods were developed for the identification of these states, unraveling the combinatorial nature of epigenetic marks and their association to genomic functional elements and transcriptional states. Nevertheless, the precise rules defining the interplay between all these marks remain poorly characterized. In this perspective we review the current state of this research field, illustrating the power and the limitations of current approaches. Finally, we sketch future avenues of research illustrating how the adoption of specific experimental designs coupled with available experimental approaches could be critical for a significant progress in this area.
Beçak, M L
This article reviews the polyploidy events that have long been demonstrated to play a role in the evolution of Anura, while also discussing the importance of epigenetic control of gene expression and diversity. Findings on Brazilian autopolyploid anurans, mainly of the genus Odontophrynus, obtained in previous studies on their cytogenetics, chromatin ultrastructure, and molecular gene regulation are discussed here. Our data on genome duplication and on epigenetic events were analyzed here regarding phylogenetic trees, including the classic 2R model for vertebrate evolution and the growing evidence of similar epigenetic mechanisms in animal and allopolyploid plants. We propose that polyploidy and epigenetic events led to rapid Anura diversity and speciation. Also, recent advances in molecular studies in other organisms led us to revisit some controversial models of evolution.
Offermann, Sascha; Peterhansel, Christoph
Heterosis is the increase in fitness and yield of F1 hybrids derived from a cross between distantly related genotypes. The use of heterosis is one of the most successful crop breeding strategies, but the underlying molecular mechanisms are still poorly defined. There is ample evidence that heterosis is associated with increased rates of photosynthesis and recent analyses have shed light on the underlying biochemical principles. In parallel, the importance of epigenetic chromatin modifications in heterosis has now been established. The first direct links between epigenetic changes and improved photosynthesis have also been demonstrated. As epigenetic engineering is now possible, we discuss the feasibility of altering the epigenetic code to enhance photosynthesis. Copyright © 2014 Elsevier Ltd. All rights reserved.
Poplineau, Mathilde; Trussardi-Régnier, Aurélie; Happillon, Teddy; Dufer, Jean; Manfait, Michel; Bernard, Philippe; Piot, Olivier; Antonicelli, Frank
Classical biochemical and molecular methods for discerning cells with epigenetic modifications are often biologically perturbing or even destructive. We wondered whether the noninvasive laser tweezer Raman spectroscopy technique allowed the discrimination of single living human cells undergoing epigenetic modifications. Human Jurkat leukemic cells were treated with inhibitors of histone deacetylases (trichostatin A and MS-275). Epigenetic changes were monitored through histone electrophoresis, nuclear image cytometry and laser tweezer Raman spectroscopy. Treatment of Jurkat cells with histone deacetylase inhibitors increased histone acetylation and induced chromatin organization changes. Characteristic vibrations, issued from laser tweezer Raman spectroscopy analyses, mostly assigned to DNA and proteins allowed discerning histone deacetylase inhibitor-treated cells from control with high confidence. Statistical processing of laser tweezer Raman spectroscopy data led to the definition of specific biomolecular fingerprints of each cell group. This original study shows that laser tweezer Raman spectroscopy is a label-free rapid tool to identify living cells that underwent epigenetic changes.
Johnson, John L; Georgakilas, Georgios; Petrovic, Jelena; Kurachi, Makoto; Cai, Stanley; Harly, Christelle; Pear, Warren S; Bhandoola, Avinash; Wherry, E John; Vahedi, Golnaz
T cell development is orchestrated by transcription factors that regulate the expression of genes initially buried within inaccessible chromatin, but the transcription factors that establish the regulatory landscape of the T cell lineage remain unknown. Profiling chromatin accessibility at eight stages of T cell development revealed the selective enrichment of TCF-1 at genomic regions that became accessible at the earliest stages of development. TCF-1 was further required for the accessibility of these regulatory elements and at the single-cell level, it dictated a coordinate opening of chromatin in T cells. TCF-1 expression in fibroblasts generated de novo chromatin accessibility even at chromatin regions with repressive marks, inducing the expression of T cell-restricted genes. These results indicate that a mechanism by which TCF-1 controls T cell fate is through its widespread ability to target silent chromatin and establish the epigenetic identity of T cells. Copyright © 2018 Elsevier Inc. All rights reserved.
Nair, Nidhi; Shoaib, Muhammad; Sørensen, Claus Storgaard
Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote ...... of chromatin structure regulation in maintaining genome integrity by multiple mechanisms including facilitating DNA repair and directly suppressing endogenous DNA damage.......Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote...... access of relevant enzymes to specific DNA regions for signaling and repair. Furthermore, recent data highlight genome maintenance roles of chromatin through the regulation of endogenous DNA-templated processes including transcription and replication. Here, we review research that shows the importance...
Ryan A. Rapp; Jonathan F. Wendel
.... Here, we provide an introduction to epigenetic mechanisms in plants, and highlight some of the empirical studies illustrative of the possible connections between evolution and epigenetically mediated alterations in gene expression and morphology.
Yelina, Natasha; Diaz, Patrick; Lambing, Christophe; Henderson, Ian R
Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. During meiosis homologous chromosomes pair and undergo DNA double strand breaks generated by the Spo11 endonuclease. These breaks can be repaired as crossovers that result in reciprocal exchange between chromosomes. The frequency of recombination along chromosomes is highly variable, for example, crossovers are rarely observed in heterochromatin and the centromeric regions. Recent work in plants has shown that crossover hotspots occur in gene promoters and are associated with specific chromatin modifications, including H2A.Z. Meiotic chromosomes are also organized in loop-base arrays connected to an underlying chromosome axis, which likely interacts with chromatin to organize patterns of recombination. Therefore, epigenetic information exerts a major influence on patterns of meiotic recombination along chromosomes, genetic variation within populations and evolution of plant genomes.
Sabine U. Vorrink
Full Text Available Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP 1A1, are regulated by the aryl hydrocarbon receptor (AhR. 3,3',4,4',5-Penta chlorobiphenyl (PCB 126 is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that human carcinoma cell lines derived from different types of epithelial cells displayed divergent degrees of CYP1A1 induction after exposure to PCB 126. Since epigenetic mechanisms are known to be involved in cell type-specific gene expression, we sought to assess the epigenetic determinants of CYP1A1 induction in these carcinoma cell lines. In contrast to HepG2 hepatocarcinoma cells, HeLa cervical carcinoma cells showed significantly lower levels of CYP1A1 mRNA expression following PCB 126 exposure. Our results show that the two cell lines maintained differences in the chromatin architecture along the CYP1A1 promoter region. Furthermore, treatment with the epigenetic modifiers, trichostatin A (TSA and 5-aza-2'-deoxycytidine (5-Aza-dC, significantly increased the expression of CYP1A1 after PCB 126 treatment in HeLa cells. However, we did not observe apparent differences in methylation levels or specific location of CpG DNA methylation between the two cell lines in the analyzed CYP1A1 promoter region. Taken together, our findings suggest that the differences in CYP1A1 expression between HepG2 and HeLa cells are due to differences in the chromatin architecture of the CYP1A1 promoter and thus establish a role of epigenetic regulation in cell-specific CYP1A1 expression.
Gubiani, Juliana R; Wijeratne, E M Kithsiri; Shi, Taoda; Araujo, Angela R; Arnold, A Elizabeth; Chapman, Eli; Gunatilaka, A A Leslie
Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10'S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, (S,Z)-5-(3',4'-dihydroxybutyldiene)-3-propylfuran-2(5H)-one (4) together with nafuredin (5). The structure of 4 was elucidated by spectroscopic analyses and its absolute configuration was determined by application of the modified Mosher's ester method. The absolute structure of (10'S)-verruculide B was determined as 5-[(10'S,2'E,6'E)-10',11'-dihydroxy-3',7',11'-trimethyldodeca-2',6'-dien-1'-yl]-(3R)-6,8-dihydroxy-3-methylisochroman-1-one (1) with the help of CD and NOE data. Compound 1 inhibited the activity of protein tyrosine phosphatases (PTPs) 1B (PTP1B), Src homology 2-containing PTP 1 (SHP1) and T-cell PTP (TCPTP) with IC50 values of 13.7±3.4, 8.8±0.6, and 16.6±3.8μM, respectively. Significance of these activities and observed modest selectivity of 1 for SHP1 over PTP1B and TCPTP is discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.
Golledge, Jonathan; Biros, Erik; Bingley, John; Iyer, Vikram; Krishna, Smriti M
The term epigenetics is usually used to describe inheritable changes in gene function which do not involve changes in the DNA sequence. These typically include non-coding RNAs, DNA methylation and histone modifications. Smoking and older age are recognised risk factors for peripheral artery diseases, such as occlusive lower limb artery disease and abdominal aortic aneurysm, and have been implicated in promoting epigenetic changes. This brief review describes studies that have associated epigenetic factors with peripheral artery diseases and investigations which have examined the effect of epigenetic modifications on the outcome of peripheral artery diseases in mouse models. Investigations have largely focused on microRNAs and have identified a number of circulating microRNAs associated with human peripheral artery diseases. Upregulating or antagonising a number of microRNAs has also been reported to limit aortic aneurysm development and hind limb ischemia in mouse models. The importance of DNA methylation and histone modifications in peripheral artery disease has been relatively little studied. Whether circulating microRNAs can be used to assist identification of patients with peripheral artery diseases and be modified in order to improve the outcome of peripheral artery disease will require further investigation.
Tanaka, Minoru; Roberts, Justin M; Qi, Jun; Bradner, James E
Gene regulatory pathways comprise an emerging and active area of chemical probe discovery and investigational drug development. Emerging insights from cancer genome sequencing and chromatin biology have identified leveraged opportunities for development of chromatin-directed small molecules as cancer therapies. At present, only six agents in two epigenetic target classes have been approved by the US FDA, limited to treatment of hematological malignancies. Recently, new classes of epigenetic inhibitors have appeared in literatures. First-in-class compounds have successfully transitioned to clinical investigation, importantly also in solid tumors and pediatric malignancies. This review considers patent applications for small-molecule inhibitors of selected epigenetic targets from 2010 to 2014. Included are exemplary classes of chromatin-associated epigenomic writers (DOT1L and EZH2), erasers (LSD1) and readers (BRD4).
Klein, C B; Costa, M
This paper will explore emerging concepts related to alternative carcinogenic mechanisms of 'non-mutagenic,' and hence epigenetic, carcinogens that may heritably alter DNA methylation without changing the underlying DNA sequence. In this review, we will touch on the basic concepts of DNA methylation, and will elaborate in greater detail on related topics including chromatin condensation, and heterochromatin spreading that is well known to induce gene silencing by position effect variegation in Drosophila and other species. Data from our model transgenic G12 cell system will be presented to support our hypothesis that certain carcinogens, such as nickel, may be carcinogenic not primarily because of their overt mutability, but rather as the result of their ability to promote DNA hypermethylation of important cancer-related genes. We will conclude with a discussion of the broader relevance of our findings and its application to other so-called 'epigenetic' carcinogens.
Thomas C Roberts
Full Text Available Myostatin (Mstn is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as Duchenne muscular dystrophy. Here we describe a novel Mstn blockade approach in which small interfering RNAs (siRNAs complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS in two differentiated mouse muscle cell lines. Silencing is sensitive to treatment with the histone deacetylase inhibitor trichostatin A, and the silent state chromatin mark H3K9me2 is enriched at the Mstn promoter following siRNA transfection, suggesting epigenetic remodeling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for Mstn and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders.
McKeown, Peter C; Spillane, Charles
The understanding of epigenetic mechanisms is necessary for assessing the potential impacts of epigenetics on plant growth, development and reproduction, and ultimately for the response of these factors to evolutionary pressures and crop breeding programs. This volume highlights the latest in laboratory and bioinformatic techniques used for the investigation of epigenetic phenomena in plants. Such techniques now allow genome-wide analyses of epigenetic regulation and help to advance our understanding of how epigenetic regulatory mechanisms affect cellular and genome function. To set the scene, we begin with a short background of how the field of epigenetics has evolved, with a particular focus on plant epigenetics. We consider what has historically been understood by the term "epigenetics" before turning to the advances in biochemistry, molecular biology, and genetics which have led to current-day definitions of the term. Following this, we pay attention to key discoveries in the field of epigenetics that have emerged from the study of unusual and enigmatic phenomena in plants. Many of these phenomena have involved cases of non-Mendelian inheritance and have often been dismissed as mere curiosities prior to the elucidation of their molecular mechanisms. In the penultimate section, consideration is given to how advances in molecular techniques are opening the doors to a more comprehensive understanding of epigenetic phenomena in plants. We conclude by assessing some opportunities, challenges, and techniques for epigenetic research in both model and non-model plants, in particular for advancing understanding of the regulation of genome function by epigenetic mechanisms.
Sartor, Gregory C; Powell, Samuel K; Brothers, Shaun P; Wahlestedt, Claes
Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic "reader" proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self-administration. Systemic and intra-accumbal inhibition of BRD4 with the BET inhibitor, JQ1, attenuated the rewarding effects of cocaine in a conditioned place preference procedure but did not affect conditioned place aversion, nor did JQ1 alone induce conditioned aversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but not BRD3, to the promoter region of Bdnf in the NAc, whereas systemic injection of JQ1 attenuated cocaine-induced expression of Bdnf in the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction. Proteins involved in the "readout" of lysine acetylation marks, referred to as BET bromodomain proteins (including BRD2, BRD3, BRD4, and BRDT), have been shown to be key regulators of chromatin dynamics and disease, and BET inhibitors are currently
Full Text Available The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS´s regulation and neurological disorders are mediated via modulation of chromatin structure.Epigenetics, introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA, nicotinamide adenine dinucleotide (NAD+ and beta hydroxybutyrate (β-HB, regulates some of these epigenetic modifications, linking in a precise way environment with gene expression.This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of
Qureshi, Irfan A.; Mehler, Mark F.
The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type–specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues. PMID:23571666
When the human genome project was completed, it revealed a surprising result. 98% of the genome did not code for protein of which more than 50% are repeats— later known as ”Junk DNA”. However, comparative genomics unveiled that many noncoding elements are evolutionarily constrained; thus luckily to have a role in genome stability and regulation. Though, their exact functions remained largely unknown. Several large international consortia such as the Functional Annotation of Mammalian Genomes (FANTOM) and the Encyclopedia of DNA Elements (ENCODE) were set to understand the structure and the regulation of the genome. Specifically, these endeavors aim to measure and reveal the transcribed components and functional elements of the genome. One of the most the striking findings of these efforts is that most of the genome is transcribed, including non-conserved noncoding elements and repeat elements. Specifically, we investigated the evolution and epigenetic properties of noncoding elements. 1. We compared genomes of evolutionarily distant species and showed the ubiquity of constrained noncoding elements in metazoa. 2. By integrating multi-omic data (such as transcriptome, nucleosome profiling, histone modifications), I conducted a comprehensive analysis of epigenetic properties (chromatin states) of conserved noncoding elements in insects. We showed that those elements have distinct and protective sequence features, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. 3. I focused on the relationship between enhancers and repetitive elements. Using Cap Analysis of Gene Expression (CAGE) and RNASeq, I compiled a full catalog of active enhancers (a class of noncoding elements) during myogenesis of human primary cells of healthy donors and donors affected by Duchenne muscular dystrophy (DMD). Comparing the two time-courses, a significant change in the epigenetic
Raabe, Florian Joachim; Spengler, Dietmar
Epidemiological and clinical studies have shown that children exposed to adverse experiences are at increased risk for the development of depression, anxiety disorders, and posttraumatic stress disorder (PTSD). A history of child abuse and maltreatment increases the likelihood of being subsequently exposed to traumatic events or of developing PTSD as an adult. The brain is highly plastic during early life and encodes acquired information into lasting memories that normally subserve adaptation. Translational studies in rodents showed that enduring sensitization of neuronal and neuroendocrine circuits in response to early life adversity are likely risk factors of life time vulnerability to stress. Hereby, the hypothalamic-pituitary-adrenal (HPA) axis integrates cognitive, behavioral, and emotional responses to early-life stress and can be epigenetically programed during sensitive windows of development. Epigenetic mechanisms, comprising reciprocal regulation of chromatin structure and DNA methylation, are important to establish and maintain sustained, yet potentially reversible, changes in gene transcription. The relevance of these findings for the development of PTSD requires further studies in humans where experience-dependent epigenetic programing can additionally depend on genetic variation in the underlying substrates which may protect from or advance disease development. Overall, identification of early-life stress-associated epigenetic risk markers informing on previous stress history can help to advance early diagnosis, personalized prevention, and timely therapeutic interventions, thus reducing long-term social and health costs.
Thomas, Merlin C
Progressive kidney disease is a common companion to both type 1 and type 2 diabetes. However, the majority of people with diabetes do not develop diabetic kidney disease. This may in part be explained by good control of glucose, blood pressure, obesity and other risk factors for kidney disease. It may also be partly due to their genetic makeup or ethnicity. However, the vast majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors or genetics. Epigenetics has recently emerged as an increasingly powerful paradigm to understand and potentially explain complex non-Mendelian conditions-including diabetic kidney disease. Persistent epigenetic changes can be acquired during development or as adaptations to environmental exposure, including metabolic fluctuations associated with diabetes. These epigenetic modifications-including DNA methylation, histone modifications, non-coding RNAs and other changes in chromatin structure and function-individually and co-operatively act to register, store, retain and recall past experiences in a way to shape the transcription of specific genes and, therefore, cellular functions. This review will explore the emerging evidence for the role of epigenetic modifications in programming the legacy of hyperglycaemia for kidney disease in diabetes.
Florian Joachim Raabe
Full Text Available Epidemiological and clinical studies have shown that children exposed to adverse experiences are at increased risk for the development of depression, anxiety disorders and PTSD. A history of child abuse and maltreatment increases the likelihood of being subsequently exposed to traumatic events or of developing PTSD as an adult. The brain is highly plastic during early life and encodes acquired information into lasting memories that normally subserve adaptation. Translational studies in rodents showed that enduring sensitization of neuronal and neuroendocrine circuits in response to early life adversity are likely risk factors of life time vulnerability to stress. Hereby, the hypothalamic-pituitary-adrenal (HPA axis integrates cognitive, behavioural and emotional responses to early-life stress and can be epigenetically programmed during sensitive windows of development. Epigenetic mechanisms, comprising reciprocal regulation of chromatin structure and DNA methylation, are important to establish and maintain sustained, yet potentially reversible, changes in gene transcription. The relevance of these findings for the development of PTSD requires further studies in humans where experience-dependent epigenetic programming can additionally depend on genetic variation in the underlying substrates which may protect from or advance disease development. Overall, identification of early-life stress associated epigenetic risk markers informing on previous stress history can help to advance early diagnosis, personalized prevention and timely therapeutic interventions, thus reducing long-term social and health costs.
Full Text Available Abstract The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. Enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases.
Epigenetics studies the emergence of different phenotypes from a single genotype. Although these processes are essential to cellular differentiation and transcriptional memory, they are also widely used in all branches of the tree of life by organisms that require plastic but stable adaptation to their physical and social environment. Because of the inherent flexibility of epigenetic regulation, a variety of biological phenomena can be traced back to evolutionary adaptations of few conserved molecular pathways that converge on chromatin. For these reasons chromatin biology and epigenetic research have a rich history of chasing discoveries in a variety of model organisms, including yeast, flies, plants and humans. Many more fascinating examples of epigenetic plasticity lie outside the realm of model organisms and have so far been only sporadically investigated at a molecular level; however, recent progress on sequencing technology and genome editing tools have begun to blur the lines between model and non-model organisms, opening numerous new avenues for investigation. Here, I review examples of epigenetic phenomena in non-model organisms that have emerged as potential experimental systems, including social insects, fish and flatworms, and are becoming accessible to molecular approaches. © 2015. Published by The Company of Biologists Ltd.
Schirmer, Eric C. [Wellcome Trust Centre for Cell Biology, University of Edinburgh, Kings Buildings, Michael Swann Building, Room 5.22, Edinburgh EH9 3JR (United Kingdom)], E-mail: firstname.lastname@example.org
Mammalian chromosomes and some specific genes have non-random positions within the nucleus that are tissue-specific and heritable. Work in many organisms has shown that genes at the nuclear periphery tend to be inactive and altering their partitioning to the interior results in their activation. Proteins of the nuclear envelope can recruit chromatin with specific epigenetic marks and can also recruit silencing factors that add new epigenetic modifications to chromatin sequestered at the periphery. Together these findings indicate that the nuclear envelope is a significant epigenetic regulator. The importance of this function is emphasized by observations of aberrant distribution of peripheral heterochromatin in several human diseases linked to mutations in NE proteins. These debilitating inherited diseases range from muscular dystrophies to the premature aging progeroid syndromes and the heterochromatin changes are just one early clue for understanding the molecular details of how they work. The architecture of the nuclear envelope provides a unique environment for epigenetic regulation and as such a great deal of research will be required before we can ascertain the full range of its contributions to epigenetics.
Zaidi, Sayyed K; Van Wijnen, Andre J; Lian, Jane B; Stein, Janet L; Stein, Gary S
Cancer is a multifaceted disease that involves acquisition of genetic mutations, deletions, and amplifications as well as deregulation of epigenetic mechanisms that fine-tune gene regulation. Key epigenetic mechanisms that include histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing are often deregulated in a variety of cancers. Subnuclear localization of key proteins in the interphase nucleus and bookmarking of genes by lineage commitment factors in mitosis-a new dimension to epigenetic control of fundamental biological processes-is also modified in cancer. In this review, we discuss the various aspects of epigenetic control that are operative in a variety of cancers and their potential for risk assessment, early detection, targeted therapy, and personalized medicine. Copyright © 2013 Wiley Periodicals, Inc.
Full Text Available The ability to regenerate complex structures is broadly represented in both plant and animal kingdoms. Although regenerative abilities vary significantly amongst metazoans, cumulative studies have identified cellular events that are broadly observed during regenerative events. For example, structural damage is recognized and wound healing initiated upon injury, which is followed by programmed cell death in the vicinity of damaged tissue and a burst in proliferation of progenitor cells. Sustained proliferation and localization of progenitor cells to site of injury give rise to an assembly of differentiating cells known as the regeneration blastema, which fosters the development of new tissue. Finally, preexisting tissue rearranges and integrates with newly differentiated cells to restore proportionality and function. While heterogeneity exists in the basic processes displayed during regenerative events in different species—most notably the cellular source contributing to formation of new tissue—activation of conserved molecular pathways is imperative for proper regulation of cells during regeneration. Perhaps the most fundamental of such molecular processes entails chromatin rearrangements, which prime large changes in gene expression required for differentiation and/or dedifferentiation of progenitor cells. This review provides an overview of known contributions to regenerative processes by noncoding RNAs and chromatin-modifying enzymes involved in epigenetic regulation.
Bonifer, Constanze; Cockerill, Peter N
During ontogeny, cells progress through multiple alternate differentiation states by activating distinct gene regulatory networks. In this review, we highlight the important role of chromatin priming in facilitating gene activation during lineage specification and in maintaining an epigenetic memory of previous gene activation. We show that chromatin priming is part of a hugely diverse repertoire of regulatory mechanisms that genes use to ensure that they are expressed at the correct time, in the correct cell type, and at the correct level, but also that they react to signals. We also emphasize how increasing our knowledge of these principles could inform our understanding of developmental failure and disease. Copyright © 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
Jason G. Wood
Full Text Available Epigenetic regulatory mechanisms are increasingly appreciated as central to a diverse array of biological processes, including aging. An association between heterochromatic silencing and longevity has long been recognized in yeast, and in more recent years evidence has accumulated of age-related chromatin changes in C. elegans, Drosophila, and mouse model systems, as well as in the tissue culture-based replicative senescence model of cell aging. In addition, a number of studies have linked expression of transposable elements (TEs, as well as changes in the RNAi pathways that cells use to combat TEs, to the aging process. This review summarizes the recent evidence linking chromatin structure and function to aging, with a particular focus on the relationship of heterochromatin structure to organismal aging.
Grob, Stefan; Grossniklaus, Ueli
Nuclear organization and higher-order chromosome structure in interphase nuclei are thought to have important effects on fundamental biological processes, including chromosome condensation, replication, and transcription. Until recently, however, nuclear organization could only be analyzed microscopically. The development of chromatin conformation capture (3C)-based techniques now allows a detailed look at chromosomal architecture from the level of individual loci to the entire genome. Here we provide a robust Hi-C protocol, allowing the analysis of nuclear organization in nuclei from different wild-type and mutant plant tissues. This method is quantitative and provides a highly efficient and comprehensive way to study chromatin organization during plant development, in response to different environmental stimuli, and in mutants disrupting a variety of processes, including epigenetic pathways regulating gene expression.
Chen, Ming; Lv, Shaolei; Meng, Yijun
Epigenetic research is at the forefront of plant biology and molecular genetics. Studies on higher plants underscore the significant role played by epigenetics in both plant development and stress response. Relatively recent advances in analytical methodology have allowed for a significant expansion of what is known about genome-wide mapping of DNA methylation and histone modifications. In this review, we explore the different modification patterns in plant epigenetics, and the key factors involved in the epigenetic process, in order to illustrate various putative mechanisms. Experimental technology to exploit these modifications, and proposed focus areas for future plant epigenetic research, are also presented.
Lee, Yun Hwa; Wu, Qiang
ES cells (embryonic stem cells) derived from the ICM (inner cell mass) of blastocysts are pluripotent and are capable of giving rise to most cell types. The ES cell identity is mainly maintained by the Oct4 (octamer-binding transcription factor 4) and Nanog transcriptional networks. Recently, a tremendous amount of work has focused on deciphering how ES cell identity is regulated epigenetically. It has been shown that histone methylation/demethylation, histone acetylation/deacetylation, histone variants and chromatin remodelling play crucial roles in ES cell maintenance and differentiation. Moreover, perturbation of those chromatin regulators results in loss of ES cell identity or aberrant differentiation. Therefore, it is important to fully understand the chromatin regulation landscape of ES cells. The knowledge gained will help us to harness the unique characteristics of ES cells for stem cell-related therapy and regenerative medicine. In the present review, we will discuss recent proceedings that provide novel insights into chromatin regulation of ES cell identity.
Full Text Available The interaction of DNA with proteins in the context of chromatin has to be tightly regulated to achieve so different tasks as packaging, transcription, replication and repair. The very rapid and transient post-translational modification of proteins by poly(ADP-ribose has been shown to take part in all four. Originally identified as immediate cellular answer to a variety of genotoxic stresses, already early data indicated the ability of this highly charged nucleic acid-like polymer to modulate nucleosome structure, the basic unit of chromatin. At the same time the enzyme responsible for synthesizing poly(ADP-ribose, the zinc-finger protein poly(ADP-ribose polymerase-1 (PARP1, was shown to control transcription initiation as basic factor TFIIC within the RNA-polymerase II machinery. Later research focused more on PARP-mediated regulation of DNA repair and cell death, but in the last few years, transcription as well as chromatin modulation has re-appeared on the scene. This review will discuss the impact of PARP1 on transcription and transcription factors, its implication in chromatin remodeling for DNA repair and probably also replication, and its role in controlling epigenetic events such as DNA methylation and the functionality of the insulator protein CCCTC-binding factor.
Full Text Available Herpesvirus latency is generally thought to be governed by epigenetic modifications, but the dynamics of viral chromatin at early timepoints of latent infection are poorly understood. Here, we report a comprehensive spatial and temporal analysis of DNA methylation and histone modifications during latent infection with Kaposi Sarcoma-associated herpesvirus (KSHV, the etiologic agent of Kaposi Sarcoma and primary effusion lymphoma (PEL. By use of high resolution tiling microarrays in conjunction with immunoprecipitation of methylated DNA (MeDIP or modified histones (chromatin IP, ChIP, our study revealed highly distinct landscapes of epigenetic modifications associated with latent KSHV infection in several tumor-derived cell lines as well as de novo infected endothelial cells. We find that KSHV genomes are subject to profound methylation at CpG dinucleotides, leading to the establishment of characteristic global DNA methylation patterns. However, such patterns evolve slowly and thus are unlikely to control early latency. In contrast, we observed that latency-specific histone modification patterns were rapidly established upon a de novo infection. Our analysis furthermore demonstrates that such patterns are not characterized by the absence of activating histone modifications, as H3K9/K14-ac and H3K4-me3 marks were prominently detected at several loci, including the promoter of the lytic cycle transactivator Rta. While these regions were furthermore largely devoid of the constitutive heterochromatin marker H3K9-me3, we observed rapid and widespread deposition of H3K27-me3 across latent KSHV genomes, a bivalent modification which is able to repress transcription in spite of the simultaneous presence of activating marks. Our findings suggest that the modification patterns identified here induce a poised state of repression during viral latency, which can be rapidly reversed once the lytic cycle is induced.
Cheng, Tsu-Fan; Choudhuri, Supratim; Muldoon-Jacobs, Kristi
The term epigenetics was coined in the context of developmental studies, but the meaning of the term has evolved over time. Epigenetic modulators of gene expression are now known to include DNA methylation, chromatin modifications and noncoding RNAs. The observation that epigenetic changes can be transmitted transgenerationally makes the science of epigenetics very relevant to the field of environmental and molecular toxicology. Heavy metals constitute an important class of environmental contaminants that have been known to influence gene expression directly by binding various metal response elements in the target gene promoters. Recent research suggests that metals can also influence gene expression through epigenetic mechanisms; this adds a new twist to the complexity of metal-mediated gene expression. Here, we review recent studies that investigate the epigenetic, gene expression, and biological effects of various inorganic and organic forms of heavy metals, such as cadmium, arsenic, nickel, chromium, methylmercury, lead, copper and organotin compounds. Copyright © 2012 John Wiley & Sons, Ltd.
Reddy, Marpadga A.; Natarajan, Rama
The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from genetic susceptibility, epigenetic mechanisms need to be evaluated to gain critical new information about kidney diseases. Epigenetics is the study of processes that control gene expression and phenotype without alterations in the underlying DNA sequence. Epigenetic modifications, including cytosine DNA methylation and covalent post translational modifications of histones in chromatin are part of the epigenome, the interface between the stable genome and the variable environment. This dynamic epigenetic layer responds to external environmental cues to influence the expression of genes associated with disease states. The field of epigenetics has seen remarkable growth in the past few years with significant advances in basic biology, contributions to human disease, as well as epigenomics technologies. Further understanding of how the renal cell epigenome is altered by metabolic and other stimuli can yield novel new insights into the pathogenesis of kidney diseases. In this review, we have discussed the current knowledge on the role of epigenetic mechanisms (primarily DNA me and histone modifications) in acute and chronic kidney diseases, and their translational potential to identify much needed new therapies. PMID:25993323
Reddy, Marpadga A; Natarajan, Rama
The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from genetic susceptibility, epigenetic mechanisms need to be evaluated to gain critical new information about kidney diseases. Epigenetics is the study of processes that control gene expression and phenotype without alterations in the underlying DNA sequence. Epigenetic modifications, including cytosine DNA methylation and covalent post-translational modifications of histones in chromatin, are part of the epigenome, the interface between the stable genome and the variable environment. This dynamic epigenetic layer responds to external environmental cues to influence the expression of genes associated with disease states. The field of epigenetics has seen remarkable growth in the past few years with significant advances in basic biology, contributions to human disease, as well as epigenomics technologies. Further understanding of how the renal cell epigenome is altered by metabolic and other stimuli can yield novel new insights into the pathogenesis of kidney diseases. In this review, we have discussed the current knowledge on the role of epigenetic mechanisms (primarily DNAme and histone modifications) in acute and chronic kidney diseases, and their translational potential to identify much needed new therapies.
Teperek, Marta; Simeone, Angela; Gaggioli, Vincent; Miyamoto, Kei; Allen, George E; Erkek, Serap; Kwon, Taejoon; Marcotte, Edward M; Zegerman, Philip; Bradshaw, Charles R; Peters, Antoine H F M; Gurdon, John B; Jullien, Jerome
For a long time, it has been assumed that the only role of sperm at fertilization is to introduce the male genome into the egg. Recently, ideas have emerged that the epigenetic state of the sperm nucleus could influence transcription in the embryo. However, conflicting reports have challenged the existence of epigenetic marks on sperm genes, and there are no functional tests supporting the role of sperm epigenetic marking on embryonic gene expression. Here, we show that sperm is epigenetically programmed to regulate embryonic gene expression. By comparing the development of sperm- and spermatid-derived frog embryos, we show that the programming of sperm for successful development relates to its ability to regulate transcription of a set of developmentally important genes. During spermatid maturation into sperm, these genes lose H3K4me2/3 and retain H3K27me3 marks. Experimental removal of these epigenetic marks at fertilization de-regulates gene expression in the resulting embryos in a paternal chromatin-dependent manner. This demonstrates that epigenetic instructions delivered by the sperm at fertilization are required for correct regulation of gene expression in the future embryos. The epigenetic mechanisms of developmental programming revealed here are likely to relate to the mechanisms involved in transgenerational transmission of acquired traits. Understanding how parental experience can influence development of the progeny has broad potential for improving human health. © 2016 Teperek et al.; Published by Cold Spring Harbor Laboratory Press.
Chung, Young Rock; Schatoff, Emma; Abdel-Wahab, Omar
Gene discovery efforts in patients with hematopoietic malignancies have brought to the forefront a series of mutations in genes thought to be involved in the epigenetic regulation of gene transcription. These mutations occur in genes known, or suspected, to play a role in modifying cytosine nucleotides on DNA and/or altering the state of histone modifications. Genes such as ASXL1, DNMT3A, EZH2, IDH1/2, MLL1, and TET2 all have been shown to be mutated and/or translocated in patients with myeloid malignancies. Intriguingly, many of the alterations affecting DNA cytosine modifications in myeloid malignancies (mutations in DNMT3A, IDH1/2, and TET2) have also been found in patients with T-cell lymphomas, and EZH2 mutations appear to be critical in T-cell acute lymphoblastic leukemia development as well. In addition, the discovery of frequent mutations in CREBBP, EP300, EZH2, and MLL2 in B-cell lymphomas suggests that epigenetic alterations play a critical role in lymphomagenesis. The purpose of this review is to present functional evidence of how alterations in these epigenetic modifiers promote hematopoietic transformation. The conclusions drawn from these data are valuable in understanding biological mechanisms and potential therapeutic targets.
Martos, Suzanne N; Tang, Wan-Yee; Wang, Zhibin
Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
Cerf, Aline; Tian, Harvey C; Craighead, Harold G
Individual chromatin molecules contain valuable genetic and epigenetic information. To date, there have not been reliable techniques available for the controlled stretching and manipulation of individual chromatin fragments for high-resolution imaging and analysis of these molecules. We report the controlled stretching of single chromatin fragments extracted from two different cancerous cell types (M091 and HeLa) characterized through fluorescence microscopy and atomic force microscopy (AFM). Our method combines soft lithography with molecular stretching to form ordered arrays of more than 250,000 individual chromatin fragments immobilized into a beads-on-a-string structure on a solid transparent support. Using fluorescence microscopy and AFM, we verified the presence of histone proteins after the stretching and transfer process.
Wesley D. Frey
Full Text Available Chromatin remodeling is a key requirement for transcriptional control of cellular differentiation. However, the factors that alter chromatin architecture in mammary stem cells (MaSCs are poorly understood. Here, we show that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for MaSC self-renewal and differentiation of mammary epithelial cells (MECs. BPTF depletion arrests cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. Moreover, genome-wide analysis of DNA accessibility following genetic or chemical inhibition, suggests a role for BPTF in maintaining the open chromatin landscape at enhancers regions in MECs. Collectively, our study implicates BPTF in maintaining the unique epigenetic state of MaSCs.
Stotz, Karola; Griffiths, Paul
Everyone has heard of 'epigenetics', but the term means different things to different researchers. Four important contemporary meanings are outlined in this paper. Epigenetics in its various senses has implications for development, heredity, and evolution, and also for medicine. Concerning development, it cements the vision of a reactive genome strongly coupled to its environment. Concerning heredity, both narrowly epigenetic and broader 'exogenetic' systems of inheritance play important roles in the construction of phenotypes. A thoroughly epigenetic model of development and evolution was Waddington's aim when he introduced the term 'epigenetics' in the 1940s, but it has taken the modern development of molecular epigenetics to realize this aim. In the final sections of the paper we briefly outline some further implications of epigenetics for medicine and for the nature/nurture debate.
Pope, L.H.; Bennink, Martin L.; Greve, Jan
Recently significant success has emerged from exciting research involving chromatin stretching using optical tweezers. These experiments, in which a single chromatin fibre is attached by one end to a micron-sized bead held in an optical trap and to a solid surface or second bead via the other end,
Skinner, Michael K; Bhandari, Ramji K; Haque, M Muksitul; Nilsson, Eric E
A critical transcription factor required for mammalian male sex determination is SRY (sex determining region on the Y chromosome). The expression of SRY in precursor Sertoli cells is one of the initial events in testis development. The current study was designed to determine the impact of environmentally induced epigenetic transgenerational inheritance on SRY binding during gonadal sex determination in the male. The agricultural fungicide vinclozolin and vehicle control (DMSO) exposed gestating females (F0 generation) during gonadal sex determination promoted the transgenerational inheritance of differential DNA methylation in sperm of the F3 generation (great grand-offspring). The fetal gonads in F3 generation males were used to identify potential alterations in SRY binding sites in the developing Sertoli cells. Chromatin immunoprecipitation with an SRY antibody followed by genome-wide promoter tiling array (ChIP-Chip) was used to identify alterations in SRY binding. A total of 81 adjacent oligonucleotide sites and 173 single oligo SRY binding sites were identified to be altered transgenerationally in the Sertoli cell vinclozolin lineage F3 generation males. Observations demonstrate the majority of the previously identified normal SRY binding sites were not altered and the altered SRY binding sites were novel and new additional sites. The chromosomal locations, gene associations and potentially modified cellular pathways were investigated. In summary, environmentally induced epigenetic transgenerational inheritance of germline epimutations appears to alter the cellular differentiation and development of the precursor Sertoli cell SRY binding during gonadal sex determination that influence the developmental origins of adult onset testis disease.
Zhao, Baobing; Yang, Jing; Ji, Peng
Mammalian terminal erythropoiesis involves gradual but dramatic chromatin condensation steps that are essential for cell differentiation. Chromatin and nuclear condensation is followed by a unique enucleation process, which is believed to liberate more spaces for hemoglobin enrichment and enable the generation of a physically flexible mature red blood cell. Although these processes have been known for decades, the mechanisms are still unclear. Our recent study reveals an unexpected nuclear opening formation during mouse terminal erythropoiesis that requires caspase-3 activity. Major histones, except H2AZ, are partially released from the opening, which is important for chromatin condensation. Block of the nuclear opening through caspase inhibitor or knockdown of caspase-3 inhibits chromatin condensation and enucleation. We also demonstrate that nuclear opening and histone release are cell cycle regulated. These studies reveal a novel mechanism for chromatin condensation in mammalia terminal erythropoiesis.
Full Text Available The discovery and adaption of bacterial clustered regularly interspaced short palindromic repeats (CRISPR–CRISPR-associated (Cas systems has revolutionized the way researchers edit genomes. Engineering of catalytically inactivated Cas variants (nuclease-deficient or nuclease-deactivated [dCas] combined with transcriptional repressors, activators, or epigenetic modifiers enable sequence-specific regulation of gene expression and chromatin state. These CRISPR–Cas-based technologies have contributed to the rapid development of disease models and functional genomics screening approaches, which can facilitate genetic target identification and drug discovery. In this short review, we will cover recent advances of CRISPR–dCas9 systems and their use for transcriptional repression and activation, epigenome editing, and engineered synthetic circuits for complex control of the mammalian genome.
Luo, Huaibing; Xi, Yanping; Li, Wei; Li, Jin; Li, Yan; Dong, Shihua; Peng, Lina; Liu, Yaping; Yu, Wenqiang
Genetic and epigenetic information are faithfully duplicated and accurately transmitted to daughter cells to preserve cell identity during the cell cycle. However, how the chromatin-based epigenetic information beyond DNA sequence is stably transmitted along with the disruption and re-establishment of chromatin structure within a cell cycle remains largely unexplored. Through comprehensive analysis DNA methylation and nucleosome positioning patterns of HepG2 cells in G0/G1, early S, late S and G2/M phases, we found that DNA methylation may act as the prime element for epigenetic inheritance after replication, as DNA methylation was extremely stable in each cell cycle phase, while nucleosome occupancy showed notable phase dependent fluctuation. Nucleosome-Secured Regions (NSRs) occupied by polycomb-repressed chromatin played a role in repressing the irrelevant cell type-specific genes and were essential for preventing irrelevant transcription factors binding, while the well-defined Nucleosome-Depleted Regions (NDRs) marked the genes crucial for cell identity maintenance. Chromatin structure at NSRs and NDRs was well maintained throughout the cell cycle, which played crucial roles in steadily preserving the transcriptional identity of the cell to fulfill cell identity maintenance. Collectively, our results demonstrated that while chromatin architecture underwent dynamic changes during cell cycle progression, DNA methylation together with NSRs and NDRs were stable epigenetic elements that were required for faithful transmission to the daughter cell to accurately maintain cell identity during the cell cycle. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Milagro-Yoldi, F.I. (Fermín Ignacio); Mansego-Talavera, M.L. (María Luisa); Miguel, C.; Martinez, J. A.
Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic pl...
Tao, Zeng; Shen, Lisha; Gu, Xiaofeng; Wang, Yizhong; Yu, Hao; He, Yuehui
Epigenetic modifications, including chromatin modifications and DNA methylation, have a central role in the regulation of gene expression in plants and animals. The transmission of epigenetic marks is crucial for certain genes to retain cell lineage-specific expression patterns and maintain cell fate. However, the marks that have accumulated at regulatory loci during growth and development or in response to environmental stimuli need to be deleted in gametes or embryos, particularly in organisms such as plants that do not set aside a germ line, to ensure the proper development of offspring. In Arabidopsis thaliana, prolonged exposure to cold temperatures (winter cold), in a process known as vernalization, triggers the mitotically stable epigenetic silencing of the potent floral repressor FLOWERING LOCUS C (FLC), and renders plants competent to flower in the spring; however, this silencing is reset during each generation. Here we show that the seed-specific transcription factor LEAFY COTYLEDON1 (LEC1) promotes the initial establishment of an active chromatin state at FLC and activates its expression de novo in the pro-embryo, thus reversing the silenced state inherited from gametes. This active chromatin state is passed on from the pro-embryo to post-embryonic life, and leads to transmission of the embryonic memory of FLC activation to post-embryonic stages. Our findings reveal a mechanism for the reprogramming of embryonic chromatin states in plants, and provide insights into the epigenetic memory of embryonic active gene expression in post-embryonic phases, through which an embryonic factor acts to 'control' post-embryonic development processes that are distinct from embryogenesis in plants.
Deng, Xiang; Zhironkina, Oxana A; Cherepanynets, Varvara D; Strelkova, Olga S; Kireev, Igor I; Belmont, Andrew S
In higher eukaryotic interphase nuclei, the 100- to >1,000-fold linear compaction of chromatin is difficult to reconcile with its function as a template for transcription, replication, and repair. It is challenging to imagine how DNA and RNA polymerases with their associated molecular machinery would move along the DNA template without transient decondensation of observed large-scale chromatin "chromonema" fibers . Transcription or "replication factory" models , in which polymerases remain fixed while DNA is reeled through, are similarly difficult to conceptualize without transient decondensation of these chromonema fibers. Here, we show how a dynamic plasticity of chromatin folding within large-scale chromatin fibers allows DNA replication to take place without significant changes in the global large-scale chromatin compaction or shape of these large-scale chromatin fibers. Time-lapse imaging of lac-operator-tagged chromosome regions shows no major change in the overall compaction of these chromosome regions during their DNA replication. Improved pulse-chase labeling of endogenous interphase chromosomes yields a model in which the global compaction and shape of large-Mbp chromatin domains remains largely invariant during DNA replication, with DNA within these domains undergoing significant movements and redistribution as they move into and then out of adjacent replication foci. In contrast to hierarchical folding models, this dynamic plasticity of large-scale chromatin organization explains how localized changes in DNA topology allow DNA replication to take place without an accompanying global unfolding of large-scale chromatin fibers while suggesting a possible mechanism for maintaining epigenetic programming of large-scale chromatin domains throughout DNA replication. Copyright © 2016 Elsevier Ltd. All rights reserved.
Chen, Danqi; Fang, Lei; Mei, Shenglin; Li, Hongjie; Xu, Xia; Des Marais, Thomas L; Lu, Kun; Liu, X Shirley; Jin, Chunyuan
Formaldehyde (FA) is an environmental and occupational chemical carcinogen. Recent studies have shown that exogenous FA causes only a modest increase in DNA adduct formation compared with the amount of adducts formed by endogenous FA, raising the possibility that epigenetic mechanisms may contribute to FA-mediated carcinogenicity. We investigated the effects of FA exposure on histone modifications and chromatin assembly. We also examined the role of defective chromatin assembly in FA-mediated transcription and cell transformation. Cellular fractionation and Western blot analysis were used to measure the levels of histone modifications in human bronchial epithelial BEAS-2B cells and human nasal RPMI2650 cells in the presence of FA. Chromatin immunoprecipitation (ChIP) and micrococcal nuclease (MNase) digest assays were performed to examine the changes in chromatin assembly and accessibility after FA exposure. RNA sequencing (RNA-seq) and real-time polymerase chain reaction (PCR) were used to examine transcriptional dysregulation. Finally, anchorage-independent cell growth ability was tested by soft agar assay following FA exposure. Exposure to FA dramatically decreased the acetylation of the N-terminal tails of cytosolic histones. These modifications are important for histone nuclear import and subsequent chromatin assembly. Histone proteins were depleted in both the chromatin fraction and at most of the genomic loci tested following FA exposure, suggesting that FA compromises chromatin assembly. Moreover, FA increased chromatin accessibility and altered the expression of hundreds of cancer-related genes. Knockdown of the histone H3.3 gene (an H3 variant), which mimics inhibition of chromatin assembly, facilitated FA-mediated anchorage-independent cell growth. We propose that the inhibition of chromatin assembly represents a novel mechanism of cell transformation induced by the environmental and occupational chemical carcinogen FA. https://doi.org/10.1289/EHP1275.
Hardy, Tabitha M; Tollefsbol, Trygve O
A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an 'epigenetic diet'. Bioactive nutritional components of an epigenetic diet may be incorporated into one's regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies.
Full Text Available Centromeres, sites of kinetochore assembly, are important for chromosome stability and integrity. Most eukaryotes have regional centromeres epigenetically specified by the presence of the histone H3 variant CENP-A. CENP-A chromatin is often surrounded by pericentromeric regions packaged into transcriptionally silent heterochromatin. Candida albicans, the most common human fungal pathogen, possesses small regional centromeres assembled into CENP-A chromatin. The chromatin state of C. albicans pericentromeric regions is unknown. Here, for the first time, we address this question. We find that C. albicans pericentromeres are assembled into an intermediate chromatin state bearing features of both euchromatin and heterochromatin. Pericentromeric chromatin is associated with nucleosomes that are highly acetylated, as found in euchromatic regions of the genome, and hypomethylated on H3K4, as found in heterochromatin. This intermediate chromatin state is inhibitory to transcription and partially represses expression of proximal genes and inserted marker genes. Our analysis identifies a new chromatin state associated with pericentromeric regions.
Sinha, Puja; Singh, Kiran; Sachan, Manisha
DNA methylation is a major epigenetic modification, playing a crucial role in the development and differentiation of higher organisms. DNA methylation is also known to regulate transcription by gene repression. Various developmental genes such as c-mos, HoxB5, Sox11, and Sry show tissue-specific gene expression that was shown to be regulated by promoter DNA methylation. The aim of the present study is to investigate the establishment of chromatin marks (active or repressive) in relation to heterogeneous methylation in the promoter regions of these developmentally important genes. Chromatin-immunoprecipitation (ChIP) assays were performed to immuno-precipitate chromatin by antibodies against both active (H3K4me3) and repressive (H3K9me3) chromatin regions. The analysis of ChIP results showed that both the percentage input and fold enrichment of activated chromatin was higher in tissues expressing the respective genes as compared to the tissues not expressing the same set of genes. This was true for all the genes selected for the study (c-mos, HoxB5, Sox11, and Sry). These findings illustrate that inconsistent DNA methylation patterns (sporadic, mosaic and heterogeneous) may also influence gene regulation, thereby resulting in the modulation of chromatin conformation. These findings illustrate that various patterns of DNA methylation (asynchronous, mosaic and heterogeneous) correlates with chromatin modification, resulting in the gene regulation.
Peters, Antoine H F M; Schwaller, Juerg
Acute leukemia is characterized by clonal expansion of hematopoietic stem and progenitor cells with blocked differentiation. Clinical and experimental evidences suggest that acute myeloid leukemia (AML) is the product of several functionally cooperating genetic alterations including chromosomal translocations leading to expression of leukemogenic fusion proteins. Several AML-associated lesions target chromatin regulators like histone methyltransferases or histone acetyltransferases, including mixed-lineage leukemia 1 (MLL1) or CREB bindung protein/p300. Molecular and biochemical studies start to provide useful insights into the mechanisms of targeting and mode-of-action of such leukemogenic fusion proteins resulting in aberrant gene expression programs and AML. Chromatin modulating mechanisms are also mediating the transforming activity of key drivers of leukemogenesis by aberrant recruitment of corepressors. Recent large-scale screening efforts demonstrated that both aberrant DNA promoter methylation and aberrantly expressed microRNAs play an important role in the pathogenesis of AML as well. Current efforts to therapeutically exploit the potential reversibility of epigenetic mechanisms are focused on small molecules that inhibit DNA methyltransferases or histone deacetylases. Several phase I/II clinical trials using such compounds have reported promising, but mostly transient, clinical responses. This underscores the need to further dissect the molecular players of epigenetic mechanisms driving induction, maintenance, and potential reversibility of leukemic state to develop efficient and long-lasting targeted therapeutic strategies.
Rother, Magdalena B; van Attikum, Haico
Proper signalling and repair of DNA double-strand breaks (DSB) is critical to prevent genome instability and diseases such as cancer. The packaging of DNA into chromatin, however, has evolved as a mere obstacle to these DSB responses. Posttranslational modifications and ATP-dependent chromatin remodelling help to overcome this barrier by modulating nucleosome structures and allow signalling and repair machineries access to DSBs in chromatin. Here we recap our current knowledge on how ATP-dependent SMARCA- and CHD-type chromatin remodellers alter chromatin structure during the signalling and repair of DSBs and discuss how their dysfunction impacts genome stability and human disease.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. © 2017 The Authors.
Nutrients can reverse or change epigenetic phenomena such as DNA methylation and histone modifications, thereby modifying the expression of critical genes associated with physiologic and pathologic processes, including embryonic development, aging, and carcinogenesis. It appears that nutrients and b...
Hershkovitz, M; Riggs, A D
We report that ligation-mediated PCR (LMPCR) can be used for high-resolution study of metaphase chromosomes, and we discuss the role of metaphase chromatin structure in the preservation of differentiated cell states. The X chromosome-linked human PGK1 (phosphoglycerate kinase 1) promoter region was investigated, and euchromatic active X chromosome (Xa) metaphase chromatin was compared with interphase Xa chromatin and to heterochromatic inactive X chromosome (Xi) metaphase and interphase chromatin. We find that (i) good-quality data at single-nucleotide resolution can be obtained by LMPCR analysis of dimethyl sulfate-treated intact metaphase cells; (ii) transcription factors present on the Xa promoter of interphase chromatin are not present on metaphase chromatin, establishing that the transcription complex on the PGK1 promoter must form de novo each cell generation; and (iii) the dimethyl sulfate reactivity pattern of Xa and Xi chromatin at metaphase is very similar to that of naked DNA. These results are discussed in the context of models for heritable chromatin structure and epigenetic mechanisms for cell memory, and they are also relevant to more general aspects of chromatin structure and differences between euchromatin and heterochromatin.
Han, Soon-Ki; Wagner, Doris
As sessile organisms, plants are exposed to environmental stresses throughout their life. They have developed survival strategies such as developmental and morphological adaptations, as well as physiological responses, to protect themselves from adverse environments. In addition, stress sensing triggers large-scale transcriptional reprogramming directed at minimizing the deleterious effect of water stress on plant cells. Here, we review recent findings that reveal a role of chromatin in water stress responses. In addition, we discuss data in support of the idea that chromatin remodelling and modifying enzymes may be direct targets of stress signalling pathways. Modulation of chromatin regulator activity by these signaling pathways may be critical in minimizing potential trade-offs between growth and stress responses. Alterations in the chromatin organization and/or in the activity of chromatin remodelling and modifying enzymes may furthermore contribute to stress memory. Mechanistic insight into these phenomena derived from studies in model plant systems should allow future engineering of broadly drought-tolerant crop plants that do not incur unnecessary losses in yield or growth. © The Author 2013. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: firstname.lastname@example.org.
Full Text Available Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc. is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.
Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis
Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches. PMID:22536485
Rando, Oliver J.; Winston, Fred
Understanding the mechanisms by which chromatin structure controls eukaryotic transcription has been an intense area of investigation for the past 25 years. Many of the key discoveries that created the foundation for this field came from studies of Saccharomyces cerevisiae, including the discovery of the role of chromatin in transcriptional silencing, as well as the discovery of chromatin-remodeling factors and histone modification activities. Since that time, studies in yeast have continued to contribute in leading ways. This review article summarizes the large body of yeast studies in this field. PMID:22345607
Over the last decade a shift in paradigm has occurred with respect to the interaction between environment and genes. It is now clear that animal genomes are regulated to a large extent as a result of input from environmental events and experiences, which cause short- and long-term modifications in epigenetic markings of DNA and histones. In this review, the evidence that such epigenetic modifications can affect the behaviour of animals is explored, and whether such acquired behaviour alterations can transfer across generation borders. First, the mechanisms by which experiences cause epigenetic modifications are examined. This includes, for example, methylation of cytosine in CpG positions and acetylation of histones, and studies showing that this can be modified by early experiences. Secondly, the evidence that specific modifications in the epigenome can be the cause of behaviour variation is reviewed. Thirdly, the extent to which this phenotypically active epigenetic variants can be inherited either through the germline or through reoccurring environmental conditions is examined. A particularly interesting observation is that epigenetic modifications are often linked to stress, and may possibly be mediated by steroid effects. Finally, the idea that transgenerationally stable epigenetic variants may serve as substrates for natural selection is explored, and it is speculated that they may even predispose for directed, non-random mutations. Copyright © 2013 Elsevier Ltd. All rights reserved.
Prachayasittikul, Veda; Prathipati, Philip; Pratiwi, Reny; Phanus-Umporn, Chuleeporn; Malik, Aijaz Ahmad; Schaduangrat, Nalini; Seenprachawong, Kanokwan; Wongchitrat, Prapimpun; Supokawej, Aungkura; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin
Epigenetic modification has been implicated in a wide range of diseases and the ability to modulate such systems is a lucrative therapeutic strategy in drug discovery. Areas covered: This article focuses on the concepts and drug discovery aspects of epigenomics. This is achieved by providing a survey of the following concepts: (i) factors influencing epigenetics, (ii) diseases arising from epigenetics, (iii) epigenetic enzymes as druggable targets along with coverage of existing FDA-approved drugs and pharmacological agents, and (iv) drug repurposing/repositioning as a means for rapid discovery of pharmacological agents targeting epigenetics. Expert opinion: Despite significant interests in targeting epigenetic modifiers as a therapeutic route, certain classes of target proteins are heavily studied while some are less characterized. Thus, such orphan target proteins are not yet druggable with limited report of active modulators. Current research points towards a great future with novel drugs directed to the many complex multifactorial diseases of humans, which are still often poorly understood and difficult to treat.
Foley, Debra L.; Craig, Jeffrey M.; Morley, Ruth; Olsson, Craig J.; Dwyer, Terence; Smith, Katherine; Saffery, Richard
Epigenetic modification can mediate environmental influences on gene expression and can modulate the disease risk associated with genetic variation. Epigenetic analysis therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. The spatial and temporal variance in epigenetic profile is of particular relevance for developmental epidemiology and the study of aging, including the variable age at onset for man...
Guo, Mingzhou; Yan, Wenji
Epigenetic changes frequently occur in human gastric cancer. Gene promoter region hypermethylation, genomic global hypomethylation, histone modifications, and alterations of noncoding RNAs are major epigenetic changes in gastric cancer. As a key risk factor of gastric cancer, H. pylori infection is an independent predictive indicator of gene methylation. A growing number of epigenetic studies in gastric cancer have provided lots of potential diagnostic and prognostic markers and therapeutic targets.
Full Text Available The activity state of a gene is determined by a complex regulatory network of co-acting factors affecting the structure of the chromatin into which the gene is embedded. While significant changes of the transcriptome occur during cell differentiation in apicomplexan parasites, basic mechanisms controlling gene expression are still unknown. Recent studies support and expand the concept of the chromatin environment being key factor for the control of transcriptional activity in these lower eukaryotes organisms. Here, we review recent advances in the field of epigenetic gene regulation in Toxoplasma gondii, the model apicomplexan.
Ibeagha-Awemu, Eveline M; Zhao, Xin
Improvement in animal productivity has been achieved over the years through careful breeding and selection programs. Today, variations in the genome are gaining increasing importance in livestock improvement strategies. Genomic information alone, however, explains only a part of the phenotypic variance in traits. It is likely that a portion of the unaccounted variance is embedded in the epigenome. The epigenome encompasses epigenetic marks such as DNA methylation, histone tail modifications, chromatin remodeling, and other molecules that can transmit epigenetic information such as non-coding RNA species. Epigenetic factors respond to external or internal environmental cues such as nutrition, pathogens, and climate, and have the ability to change gene expression leading to emergence of specific phenotypes. Accumulating evidence shows that epigenetic marks influence gene expression and phenotypic outcome in livestock species. This review examines available evidence of the influence of epigenetic marks on livestock (cattle, sheep, goat, and pig) traits and discusses the potential for consideration of epigenetic markers in livestock improvement programs. However, epigenetic research activities on farm animal species are currently limited partly due to lack of recognition, funding and a global network of researchers. Therefore, considerable less attention has been given to epigenetic research in livestock species in comparison to extensive work in humans and model organisms. Elucidating therefore the epigenetic determinants of animal diseases and complex traits may represent one of the principal challenges to use epigenetic markers for further improvement of animal productivity.
Singh, Narendra Nath; Peer, Aakanksha; Nair, Sherin; Chaturvedi, Rupesh K
Much controversy has existed over the etiopathogenesis and management of oral lesions, especially oral malignancies. The knowledge of genetic basis is proving to be inadequate in the light of emerging new mechanisms termed epigenetic phenomena. The present review article aims to understand the role of epigenetic mechanisms in oral lesions. Epigenetics is the study of acquired changes in chromatin structure that arise independently of a change in the underlying deoxyribonucleic acid (DNA) nucleotide sequence. Key components involved in epigenetic regulation are DNA methylation, histone modifications and modifications in micro ribonucleic acids (miRNA). Epigenetics is a reversible system that can be affected by various environmental factors such as diet, drugs, mental stress, physical activity and addictive substances such as tobacco, nicotine and alcohol. Epigenetics may also play a role in explaining the etiopathogenesis of developmental anomalies, genetic defects, cancer as well as substance addiction (tobacco, cigarette and alcohol). Epigenetic modifications may contribute to aberrant epigenetic mechanisms seen in oral precancers and cancers. In the near future, epigenetic variations found in oral dysplastic cells can act as a molecular fingerprint for malignancies. The literature in English language was searched and a structured scientific review and meta-analysis of scientific publications from the year 2000 to year 2015 was carried out from various journals. It was observed that epigenetic marks can prove to be novel markers for early diagnosis, prognosis and treatment of oral cancers as well as other oral diseases.
Tho X. Pham
Full Text Available Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. Epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of DNA and histones. Epigenetic mechanisms, such as DNA methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as S-adenosylmethionine and acetyl-CoA. Altered expression of adipokines in obesity may be due to epigenetic changes. The goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.
Manev, Hari; Dzitoyeva, Svetlana
Mitochondria, intracellular organelles with their own genome, have been shown capable of interacting with epigenetic mechanisms in at least four different ways. First, epigenetic mechanisms that regulate the expression of nuclear genome influence mitochondria by modulating the expression of nuclear-encoded mitochondrial genes. Second, a cell-specific mitochondrial DNA content (copy number) and mitochondrial activity determine the methylation pattern of nuclear genes. Third, mitochondrial DNA variants influence the nuclear gene expression patterns and the nuclear DNA (ncDNA) methylation levels. Fourth and most recent line of evidence indicates that mitochondrial DNA similar to ncDNA also is subject to epigenetic modifications, particularly by the 5-methylcytosine and 5-hydroxymethylcytosine marks. The latter interaction of mitochondria with epigenetics has been termed 'mitochondrial epigenetics'. Here we summarize recent developments in this particular area of epigenetic research. Furthermore, we propose the term 'mitoepigenetics' to include all four above-noted types of interactions between mitochondria and epigenetics, and we suggest a more restricted usage of the term 'mitochondrial epigenetics' for molecular events dealing solely with the intra-mitochondrial epigenetics and the modifications of mitochondrial genome.
Wright, Robert; Saul, Robert A
Epigenetics, the study of functionally relevant chemical modifications to DNA that do not involve a change in the DNA nucleotide sequence, is at the interface between research and clinical medicine. Research on epigenetic marks, which regulate gene expression independently of the underlying genetic code, has dramatically changed our understanding of the interplay between genes and the environment. This interplay alters human biology and developmental trajectories, and can lead to programmed human disease years after the environmental exposure. In addition, epigenetic marks are potentially heritable. In this article, we discuss the underlying concepts of epigenetics and address its current and potential applicability for primary care providers.
Mackenzie R. Gavery
Full Text Available Epigenetics has attracted considerable attention with respect to its potential value in many areas of agricultural production, particularly under conditions where the environment can be manipulated or natural variation exists. Here we introduce key concepts and definitions of epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, review the current understanding of epigenetics in both fish and shellfish, and propose key areas of aquaculture where epigenetics could be applied. The first key area is environmental manipulation, where the intention is to induce an ‘epigenetic memory’ either within or between generations to produce a desired phenotype. The second key area is epigenetic selection, which, alone or combined with genetic selection, may increase the reliability of producing animals with desired phenotypes. Based on aspects of life history and husbandry practices in aquaculture species, the application of epigenetic knowledge could significantly affect the productivity and sustainability of aquaculture practices. Conversely, clarifying the role of epigenetic mechanisms in aquaculture species may upend traditional assumptions about selection practices. Ultimately, there are still many unanswered questions regarding how epigenetic mechanisms might be leveraged in aquaculture.
Full Text Available Plants have evolved sophisticated genetic and epigenetic regulatory systems to respond quickly to unfavorable environmental conditions such as heat, cold, drought, and pathogen infections. In particular, heat greatly affects plant growth and development, immunity and circadian rhythm, and poses a serious threat to the global food supply. According to temperatures exposing, heat can be usually classified as warm ambient temperature (about 22-27℃, high temperature (27-30℃ and extremely high temperature (37-42℃, also known as heat stress for the model plant Arabidopsis thaliana. The genetic mechanisms of plant responses to heat have been well studied, mainly focusing on elevated ambient temperature-mediated morphological acclimation and acceleration of flowering, modulation of plant immunity and circadian clock by high temperatures, and thermotolerance to heat stress. Recently, great progress has been achieved on epigenetic regulation of heat responses, including DNA methylation, histone modifications, histone variants, ATP-dependent chromatin remodeling, histone chaperones, small RNAs, long non-coding RNAs and other undefined epigenetic mechanisms. These epigenetic modifications regulate the expression of heat-responsive genes and function to prevent heat-related damage. This review focuses on recent progresses regarding the genetic and epigenetic control of heat responses in plants, and pays more attention to the role of the major epigenetic mechanisms in plant heat responses. Further research perspectives are also discussed.
Marsha R Penner
Full Text Available This brief review will focus on a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be “plastic”. The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic “marks” drive aging-related cognitive dysfunction. Here we focus on this theme, reviewing current knowledge concerning epigene