Sashida, Goro; Iwama, Atsushi
Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia. Various epigenetic regulators are mutated in MDS patients, indicating that accumulation of epigenetic alterations together with genetic alterations plays a crucial role in the development of MDS.
Berko, Esther R.; Suzuki, Masako; Beren, Faygel; Lemetre, Christophe; Alaimo, Christine M.; Calder, R. Brent; Ballaban-Gil, Karen; Gounder, Batya; Kampf, Kaylee; Kirschen, Jill; Maqbool, Shahina B.; Momin, Zeineen; Reynolds, David M.; Russo, Natalie; Shulman, Lisa; Stasiek, Edyta; Tozour, Jessica; Valicenti-McDermott, Maria; Wang, Shenglong; Abrahams, Brett S.; Hargitai, Joseph; Inbar, Dov; Zhang, Zhengdong; Buxbaum, Joseph D.; Molholm, Sophie; Foxe, John J.; Marion, Robert W.; Auton, Adam; Greally, John M.
DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact
Esther R Berko
Full Text Available DNA mutational events are increasingly being identified in autism spectrum disorder (ASD, but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement
Full Text Available BACKGROUND: Mesenchymal stem cells (MSCs hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation.
Minocherhomji, Sheroy; Hansen, Claus; Kim, Hyung-Goo
Genome instability, epigenetic remodelling and structural chromosomal rearrangements are hallmarks of cancer. However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood....... To understand the genetic-epigenetic interplay at breakpoints of chromosomal translocations disrupting CG-rich loci, we quantified epigenetic modifications at DLGAP4 (SAPAP4), a key post-synaptic density 95 (PSD95) associated gene, truncated by the chromosome translocation t(8;20)(p12;q11.23), co......-segregating with cerebellar ataxia in a five-generation family. We report significant epigenetic remodelling of the DLGAP4 locus triggered by the t(8;20)(p12;q11.23) translocation and leading to dysregulation of DLGAP4 expression in affected carriers. Disruption of DLGAP4 results in monoallelic hypermethylation...
Dayeh, Tasnim; Ling, Charlotte
β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.
Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein
Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases.
Poghosyan, Anna, E-mail: email@example.com; Patel, Jamie K.; Clifford, Rachel L.; Knox, Alan J., E-mail: firstname.lastname@example.org
Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. -- Highlights: •A regulatory mechanism of CXCL8 transcriptional control in CF airways is proposed. •There was an increased binding of NF-κB and C/EBPβ transcription factors. •There was enhanced recruitment of BET proteins to the CXCL8 promoter. •Epigenetic modifications are responsible for the aberrant CXCL8 transcription.
Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy; Reyes, Teresa M
Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Shinjo, Keiko; Kondo, Yutaka
Besides known genetic aberrations, epigenetic alterations have emerged as common hallmarks of many cancer types, including lung cancer. Epigenetics is a process involved in gene regulation, mediated via DNA methylation, histone modification, chromatin remodeling, and functional noncoding RNAs, which influences the accessibility of the underlying DNA to transcriptional regulatory factors that activate or repress expression. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Since epigenetic therapy is now in clinical use in hematopoietic diseases and undergoing trials for lung cancer, a better understanding of epigenetic abnormalities is desired. Recent technologies for high-throughput genome-wide analyses for epigenetic modifications are promising and potent tools for understanding the global dysregulation of cancer epigenetics. In this chapter, studies of epigenetic abnormality and its clinical implication in lung cancers are discussed.
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
Nguyen Quoc Vuong Tran
Full Text Available The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD and attention deficit hyperactivity disorder (ADHD, calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates, persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment.
Mather, Karen A; Kwok, John B; Armstrong, Nicola; Sachdev, Perminder S
As the population is ageing, a better understanding of the underlying causes of age-related cognitive decline (cognitive ageing) is required. Epigenetic dysregulation is proposed as one of the underlying mechanisms for cognitive ageing. We review the current knowledge on epigenetics and cognitive ageing and appraise the potential of epigenetic preventative and therapeutic interventions. Articles on cognitive ageing and epigenetics in English were identified. Epigenetic dysregulation occurs with cognitive ageing, with changes in histone post-translational modifications, DNA methylation and non-coding RNA reported. However, human studies are lacking, with most being cross-sectional using peripheral blood samples. Pharmacological and lifestyle factors have the potential to change aberrant epigenetic profiles; but few studies have examined this in relation to cognitive ageing. The relationship between epigenetic modifications and cognitive ageing is only beginning to be investigated. Epigenetic dysregulation appears to be an important feature in cognitive ageing, but whether it is an epiphenomenon or a causal factor remains to be elucidated. Clarification of the relationship between epigenetic profiles of different cell types is essential and would determine whether epigenetic marks of peripheral tissues can be used as a proxy for changes occurring in the brain. The use of lifestyle and pharmacological interventions to improve cognitive performance and quality of life of older adults needs more investigation. Copyright © 2014 John Wiley & Sons, Ltd.
LIU Wei-ren; SHI Ying-hong; PENG Yuan-fei; FAN Jia
Epigenetic changes refer to stable alterations in gene expression with no underlying modifications in the genetic sequence itself.It has become clear that not only gene variations but also epigenetic modifications may contribute to varied diseases,including cancer.This review will provide an overview of how epigenetic factors,including genomic DNA methylation,histone modifications,and miRNA regulation,contribute to hepatocellular carcinoma (HCC) dissemination,invasion,and metastasis.Additionally,the reversal of dysregulated epigenetic changes has emerged as a potential strategy for the treatment of HCC,and we will summarize the latest epigenetic therapies for HCC.
Full Text Available Emotional dysregulation is a process which consists in mitigating, intensifying or maintaining a given emotion and is the trigger for some psychological disorders. Research has shown that a anxiety control plays an important role in emotional expression and regulation and, in addition, for anorexia nervosa and, more in general, in drive for thinness. Scientific literature suggests that in anorexia nervosa there is a core of emotional dysregulation and anxiety control. The aim of this study is to explore the roles of emotional dysregulation and anxiety control as independent or third variables in a mediational regression model related to drive for thinness. 154 clinical individuals with anorexia participated in the study and all completed a set of self-report questionnaires: eating disorders inventory version 3 (EDI-3, DERS, and the anxiety control questionnaire (ACQ. The data confirmed a mediational model in which the relation between emotional dysregulation and drive for thinness is mediated by anxiety control. The current study partially supports a clinical model in which emotional dysregulation is a distal factor in eating disorders while the mediator variable anxiety control is a proximal factor in the psychopathological process underlying it.
Priyamvada, Shubha; Gomes, Rochelle; Gill, Ravinder K.; Saksena, Seema; Alrefai, Waddah A.; Pradeep K Dudeja
Inflammatory Bowel Diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing inflammatory disorders of the gastrointestinal tract. Chronic inflammation of the intestine affects the normal fluid and electrolyte absorption leading to diarrhea, the hallmark symptom of IBD. The management of IBD associated diarrhea still remains to be a challenge, and extensive studies over the last two decades have focused on investigating the molecular mechanisms underly...
Hwang, Jee-Yeon; Aromolaran, Kelly A; Zukin, R Suzanne
Epigenetic mechanisms - including DNA methylation, histone post-translational modifications and changes in nucleosome positioning - regulate gene expression, cellular differentiation and development in almost all tissues, including the brain. In adulthood, changes in the epigenome are crucial for higher cognitive functions such as learning and memory. Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases. Although these disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression. Although not somatically heritable, epigenetic modifications in neurons are dynamic and reversible, which makes them good targets for therapeutic intervention.
Full Text Available All developmental plasticity arises through epigenetic mechanisms. In this paper we focus on the nature, origins, and consequences of these mechanisms with a focus on horned beetles, an emerging model system in evolutionary developmental genetics. Specifically, we introduce the biological significance of developmental plasticity and summarize the most important facets of horned beetle biology. We then compare and contrast the epigenetic regulation of plasticity in horned beetles to that of other organisms and discuss how epigenetic mechanisms have facilitated innovation and diversification within and among taxa. We close by highlighting opportunities for future studies on the epigenetic regulation of plastic development in these and other organisms.
Full Text Available The Fragile X-related disorders are members of the Repeat Expansion Diseases, a group of genetic conditions resulting from an expansion in the size of a tandem repeat tract at a specific genetic locus. The repeat responsible for disease pathology in the Fragile X-related disorders is CGG/CCG and the repeat tract is located in the 5’ UTR of the FMR1 gene, whose protein product FMRP, is important for the proper translation of dendritic mRNAs in response to synaptic activation. There are two different pathological FMR1 allele classes that are distinguished only by the number of repeats. Premutation alleles have 55-200 repeats and confer risk of Fragile X-associated tremor/ataxia syndrome and Fragile X-associated primary ovarian insufficiency. Full mutation alleles on the other hand have >200 repeats and result in Fragile X syndrome, a disorder that affects learning and behavior. Different symptoms are seen in carriers of premutation and full mutation alleles because the repeat number has paradoxical effects on gene expression: Epigenetic changes increase transcription from premutation alleles and decrease transcription from full mutation alleles. This review will cover what is currently known about the mechanisms responsible for these changes in FMR1 expression and how they may relate to other Repeat Expansion Diseases that also show repeat-mediated changes in gene expression.
The field of epigenetics has grown explosively in the past two decades or so. As currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in DNA sequence, but alter the way that information encoded inDNAis utilized.The bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. However, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducingorganisms or mitotically in asexually reproducing ones. Such transgenerational epigenetic inheritance (TEI) raises obvious questions about a possible evolutionary role for epigenetic ‘Lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. In this review I attempt a brief overview of the periodically reviewed and debated ‘classical’ TEI phenomena and their possible implications for evolution. The review then focusses on a less-discussed, unique kind of protein-onlyepigenetic inheritance mediated by prions. Much remains to be learnt about the mechanisms, persistence and effects of TEI. The jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.
Qureshi, Irfan A; Mehler, Mark F
There have been considerable advances in uncovering the complex genetic mechanisms that underlie nervous system disease pathogenesis, particularly with the advent of exome and whole genome sequencing techniques. The emerging field of epigenetics is also providing further insights into these mechanisms. Here, we discuss our understanding of the interplay that exists between genetic and epigenetic mechanisms in these disorders, highlighting the nascent field of epigenetic epidemiology-which focuses on analyzing relationships between the epigenome and environmental exposures, development and aging, other health-related phenotypes, and disease states-and next-generation research tools (i.e., those leveraging synthetic and chemical biology and optogenetics) for examining precisely how epigenetic modifications at specific genomic sites affect disease processes.
Dias, Brian G; Maddox, Stephanie A; Klengel, Torsten; Ressler, Kerry J
Gene expression and regulation is an important sculptor of the behavior of organisms. Epigenetic mechanisms regulate gene expression not by altering the genetic alphabet but rather by the addition of chemical modifications to proteins associated with the alphabet or of methyl marks to the alphabet itself. Being dynamic, epigenetic mechanisms of gene regulation serve as an important bridge between environmental stimuli and genotype. In this review, we outline epigenetic mechanisms by which gene expression is regulated in animals and humans. Using fear learning as a framework, we then delineate how such mechanisms underlie learning and stress responsiveness. Finally, we discuss how epigenetic mechanisms might inform us about the transgenerational inheritance of behavioral traits that are being increasingly reported.
Yu, Vionnie W C; Yusuf, Rushdia Z; Oki, Toshihiko; Wu, Juwell; Saez, Borja; Wang, Xin; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J; Lee, Eunjung; Gu, Hongcang; Meissner, Alexander; Lin, Charles P; Kharchenko, Peter V; Scadden, David T
Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.
Stephen V Liu
Full Text Available Epigenetic dysregulation of gene function has been strongly implicated in carcinogenesis and is one of the mechanisms contributing to the development of lung cancer. The inherent reversibility of epigenetic alterations makes them viable therapeutic targets. Here, we review the therapeutic implications of epigenetic changes in lung cancer, and recent advances in therapeutic strategies targeting DNA methylation and histone acetylation.
Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita
Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224
showed altered expression in normal lung from F3 mice. Thus, traces of the effects of a single dose of radiation during development persist into...radiation showed a loss of global cytosine methylation in DNA from thymus , implicating profound epigenetic dysregulation (Tawa et al., 1998; Pogribny...for the carcinogenic and transgenerational effects of radiation. It is also anticipated that these epigenetic signatures will be developed as
Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in...
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 epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging. Finally, several open questions will be discussed that we believe will fuel experimental discovery.
Ho, Emily; Beaver, Laura M; Williams, David E; Dashwood, Roderick H
The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression.
Lendvai, Ágnes; Deutsch, Manuel J; Plösch, Torsten; Ensenauer, Regina
The placental metabolism can adapt to the environment throughout pregnancy to both the demands of the fetus and the signals from the mother. Such adaption processes include epigenetic mechanisms, which alter gene expression and may influence the offspring's health. These mechanisms are linked to the diversity of prenatal environmental exposures, including maternal under- or overnutrition or gestational diabetes. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that contribute to the developmental plasticity of the placenta by regulating lipid and glucose metabolism pathways, including lipogenesis, steroidogenesis, glucose transporters, and placental signaling pathways, thus representing a link between energy metabolism and reproduction. Among the PPAR isoforms, PPARγ appears to be the main modulator of mammalian placentation. Certain fatty acids and lipid-derived moieties are the natural activating PPAR ligands. By controlling the amounts of maternal nutrients that go across to the fetus, the PPARs play an important regulatory role in placenta metabolism, thereby adapting to the maternal nutritional status. As demonstrated in animal studies, maternal nutrition during gestation can exert long-term influences on the PPAR methylation pattern in offspring organs. This review underlines the current state of knowledge on the relationship between environmental factors and the epigenetic regulation of the PPARs in placenta metabolism and offspring development. Copyright © 2016 the American Physiological Society.
Vecchiola, Andrea; Lagos, Carlos F; Carvajal, Cristian A; Baudrand, Rene; Fardella, Carlos E
In the past decades, we have extended the view of aldosterone effects beyond epithelial tissues. New evidence regarding the aldosterone/mineralocorticoid receptor (MR) pathway in active metabolic tissues, including adipose tissue, has confirmed its pathogenic role in systemic inflammation, endothelial dysfunction, insulin resistance, and dyslipidemia. Obesity, a current epidemic worldwide, increases aldosterone production by several adipocyte factors such as leptin but is also associated with local aldosterone production. In addition, obesity can modulate MR activation leading to signaling dysregulation and a pro-inflammatory profile of adipocytes. Current knowledge have deciphered that this phenotypical differences of obesity may be explained, at least in part, by novel non-genomic activation of MR, new inducers of aldosterone synthesis, and probably by several epigenetic modifications. In addition, with the understanding of the complex interplay of obesity, hormones, and receptors, targeted pharmacological therapy is expected and is currently under active research.
Vijayakanthi, Nandini; Greally, John M; Rastogi, Deepa
The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children.
Stroud, Laura R.; Papandonatos, George D.; Salisbury, Amy L.; Phipps, Maureen G.; Huestis, Marilyn A.; Niaura, Raymond; Padbury, James F.; Marsit, Carmen J.; Lester, Barry M.
Epigenetic regulation of the placental glucocorticoid receptor gene ("NR3C1") was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother-infant pairs (49% MSDP-exposed; 52% minorities; ages 18-35). The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral…
Stroud, Laura R.; Papandonatos, George D.; Salisbury, Amy L.; Phipps, Maureen G.; Huestis, Marilyn A.; Niaura, Raymond; Padbury, James F.; Marsit, Carmen J.; Lester, Barry M.
Epigenetic regulation of the placental glucocorticoid receptor gene ("NR3C1") was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother-infant pairs (49% MSDP-exposed; 52% minorities; ages 18-35). The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral…
Slane, Jennifer D; Klump, Kelly L; McGue, Matthew; Iacono, G
Women with bulimia nervosa (BN) frequently have co-occurring alcohol use disorders (AUDs). Studies of shared genetic transmission of these disorders have been mixed. Personality heterogeneity among individuals with BN may explain discrepant findings. Cluster analysis has characterized women with BN in groups on the basis of personality profiles. One group, the Dysregulated cluster, characterized largely by behavioural disinhibition and emotional dysregulation may be more closely linked etiologically to AUDs. This study examined whether genetic associations between BN and AUDs are the strongest among the Dysregulated cluster. Symptoms of BN and AUDs were assessed in female twins at ages 17 and 25 years from the Minnesota Twin Family Study. Personality clusters were defined using the Multidimensional Personality Questionnaire. Twin moderation models suggested small-to-moderate common genetic transmission between BN and AUDs. However, shared genetic effects did not differ by personality cluster. Findings suggest that personality clusters are unlikely to account for inconsistent findings regarding their shared aetiology.
Iwasaki, Mayumi; Paszkowski, Jerzy
Epigenetics refers to heritable changes in patterns of gene expression that occur without alterations in DNA sequence. The epigenetic mechanisms involve covalent modifications of DNA and histones, which affect transcriptional activity of chromatin. Since chromatin states can be propagated through mitotic and meiotic divisions, epigenetic mechanisms are thought to provide heritable 'cellular memory'. Here, we review selected examples of epigenetic memory in plants and briefly discuss underlying mechanisms.
Love, John; Cooley, Vic
The International Space Station (ISS) is a state-of-the orbiting laboratory focused on advancing science and technology research. Experiments being conducted on the ISS include investigations in the emerging field of Epigenetics. Epigenetics refers to stably heritable changes in gene expression or cellular phenotype (the transcriptional potential of a cell) resulting from changes in a chromosome without alterations to the underlying DNA nucleotide sequence (the genetic code), which are caused by external or environmental factors, such as spaceflight microgravity. Molecular mechanisms associated with epigenetic alterations regulating gene expression patterns include covalent chemical modifications of DNA (e.g., methylation) or histone proteins (e.g., acetylation, phorphorylation, or ubiquitination). For example, Epigenetics ("Epigenetics in Spaceflown C. elegans") is a recent JAXA investigation examining whether adaptations to microgravity transmit from one cell generation to another without changing the basic DNA of the organism. Mouse Epigenetics ("Transcriptome Analysis and Germ-Cell Development Analysis of Mice in Space") investigates molecular alterations in organ-specific gene expression patterns and epigenetic modifications, and analyzes murine germ cell development during long term spaceflight, as well as assessing changes in offspring DNA. NASA's first foray into human Omics research, the Twins Study ("Differential effects of homozygous twin astronauts associated with differences in exposure to spaceflight factors"), includes investigations evaluating differential epigenetic effects via comprehensive whole genome analysis, the landscape of DNA and RNA methylation, and biomolecular changes by means of longitudinal integrated multi-omics research. And the inaugural Genes in Space student challenge experiment (Genes in Space-1) is aimed at understanding how epigenetics plays a role in immune system dysregulation by assaying DNA methylation in immune cells
Full Text Available Rheumatoid arthritis (RA is a chronic inflammatory autoimmune disease that is characterized by synovial hyperplasia and progressive joint destruction. The activation of RA synovial fibroblasts (SFs, also called fibroblast-like synoviocytes (FLS, contributes significantly to perpetuation of the disease. Genetic and environmental factors have been reported to be involved in the etiology of RA but are insufficient to explain it. In recent years, accumulating results have shown the potential role of epigenetic mechanisms, including histone modifications, DNA methylation, and microRNAs, in the development of RA. Epigenetic mechanisms regulate chromatin state and gene transcription without any change in DNA sequence, resulting in the alteration of phenotypes in several cell types, especially RASFs. Epigenetic changes possibly provide RASFs with an activated phenotype. In this paper, we review the roles of epigenetic mechanisms relevant for the progression of RA.
The rapidly emerging science of epigenetics and epigenomic medicine promises to reveal novel insights into the susceptibility to and the onset and progression of epileptic disorders. Epigenetic regulatory mechanisms are now implicated in orchestrating aspects of neural development (e.g., cell fate specification and maturation), homeostasis and stress responses (e.g., immediate early gene transcription), and neural network function (e.g., excitation-inhibition coupling and activity-dependent p...
Renauer, Paul; Coit, Patrick; Sawalha, Amr H
Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.
J. David Sterns
Full Text Available Type II diabetes mellitus (T2DM is a widespread metabolic disorder characterized by insulin resistance resulting in abnormally high blood glucose levels. While the onset of T2DM is known to be influenced by a number of genetic factors, emerging research has demonstrated the additional role of a variety of epigenetic mechanisms in the development of this disorder. Epigenetics relates to the heritable changes in gene expression that cannot be explained by simple variations in the primary DNA sequence and includes DNA methylation and histone modification. These changes impact many processes, including stem cell differentiation into pancreatic endocrine cells as well as normal β-cell function. Recent studies focusing on the effects of maternal health, specifically as it is affected by famine and hyperglycemia, have found possible mechanisms to explain the increased likelihood of the fetus developing risk factors such as altered atherogenic lipid profiles, increased obesity and BMI, as well as impaired glucose tolerance (IGT for the development of T2DM later in life. It is suggested that these epigenetic influences happen early during gestation and are less susceptible to the effects of postnatal environmental modification as was previously thought. Regardless, emerging research into epigenetic-based treatment approaches for T2DM are promising and offer yet another means by which to limit the impact of this global epidemic.
Qureshi, Irfan A; Mehler, Mark F
The rapidly emerging science of epigenetics and epigenomic medicine promises to reveal novel insights into the susceptibility to and the onset and progression of epileptic disorders. Epigenetic regulatory mechanisms are now implicated in orchestrating aspects of neural development (e.g., cell fate specification and maturation), homeostasis and stress responses (e.g., immediate early gene transcription), and neural network function (e.g., excitation-inhibition coupling and activity-dependent plasticity). These same neurobiological processes are responsible for determining the heterogeneous features of complex epileptic disease states. Thus, we highlight recent evidence that is beginning to elucidate the specific roles played by epigenetic mechanisms, including DNA methylation, histone code modifications and chromatin remodeling, noncoding RNAs and RNA editing, in human epilepsy syndromes and in the process of epileptogenesis. The highly integrated layers of the epigenome are responsible for the cell type specific and exquisitely environmentally responsive deployment of genes and functional gene networks that underlie the molecular pathophysiology of epilepsy and its associated comorbidities, including but not limited to neurotransmitter receptors (e.g., GluR2, GLRA2, and GLRA3), growth factors (e.g., BDNF), extracellular matrix proteins (e.g., RELN), and diverse transcriptional regulators (e.g., CREB, c-fos, and c-jun). These important observations suggest that future epigenetic studies are necessary to better understand, classify, prevent, and treat epileptic disorders.
Joo Ho Lee
Full Text Available Non-alcoholic fatty liver disease (NAFLD is defined as a pathologic accumulation of fat in the form of triglycerides (TG in the liver (steatosis that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the excessive fat accumulation (steatohepatitis, which is referred to as non-alcoholic steatohepatitis (NASH. Patients with NASH may develop cirrhosis and hepatocellular carcinoma (HCC. NAFLD shares the key features of metabolic syndrome including obesity, hyperlipidemia, hypertension, and insulin resistance. The pathogenesis of NAFLD is multi-factorial, however the oxidative stress seems to plays a major role in the development and progression of the disease. The emerging field of epigenetics provides a new perspective on the pathogenesis of NAFLD. Epigenetics is an inheritable but reversible phenomenon that affects gene expression without altering the DNA sequence and refers to DNA methylation, histone modifications and microRNAs. Epigenetic manipulation through metabolic pathways such as one-carbon metabolism has been proposed as a promising approach to retard the progression of NAFLD. Investigating the epigenetic modifiers in NAFLD may also lead to the development of preventive or therapeutic strategies for NASH-associated complications.
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.
Villeneuve, Louisa M; Reddy, Marpadga A; Natarajan, Rama
1. Increasing evidence suggests that epigenetic factors might regulate the complex interplay between genes and the environment, and affect human diseases, such as diabetes and its complications. 2. Clinical trials have underscored the long lasting beneficial effects of strict glycaemic control for reducing the progression of diabetic complications. They have also shown that diabetic complications, such as diabetic nephropathy, a chronic kidney disorder, can continue even after blood glucose normalization, suggesting a metabolic memory of the prior glycaemic state. 3. Dysregulation of epigenetic post-transcriptional modifications of histones in chromatin, including histone lysine methylation, has been implicated in aberrant gene regulation associated with the pathology of diabetes and its complications. Genome-wide studies have shown cell-type specific changes in histone methylation patterns under diabetic conditions. In addition, studies in vascular cells have shown long lasting changes in epigenetic modifications at key inflammatory gene promoters after prior exposure to diabetic conditions, suggesting a possible mechanism for metabolic memory. 4. Recent studies have shown roles for histone methylation, DNA methylation, as well as microRNA in diabetic nephropathy. Whether these epigenetic factors play a role in metabolic memory of diabetic kidney disease is less well understood. 5. The incidence of diabetes is growing rapidly, as also the cost of treating the resulting complications. A better understanding of metabolic memory and the potential involvement of epigenetic mechanisms in this phenomenon could enable the development of new therapeutic targets for the treatment and/or prevention of sustained diabetic complications.
González, Rodrigo M; Ricardi, Martiniano M; Iusem, Norberto D
Tolerance to water deficits was evolutionarily relevant to the conquest of land by primitive plants. In this context, epigenetic events may have played important roles in the establishment of drought stress responses. We decided to inspect epigenetic marks in the plant organ that is crucial in the sensing of drought stress: the root. Using tomato as a crop model plant, we detected the methylated epialleles of Asr2, a protein-coding gene widespread in the plant kingdom and thought to alleviate restricted water availability. We found 3 contexts (CG, CNG, and CNN) of methylated cytosines in the regulatory region of Solanum lycopersicum Asr2 but only one context (CG) in the gene body. To test the hypothesis of a link between epigenetics marks and the adaptation of plants to drought, we explored the cytosine methylation status of Asr2 in the root resulting from water-deficit stress conditions. We found that a brief exposure to simulated drought conditions caused the removal of methyl marks in the regulatory region at 77 of the 142 CNN sites. In addition, the study of histone modifications around this model gene in the roots revealed that the distal regulatory region was rich in H3K27me3 but that its abundance did not change as a consequence of stress. Additionally, under normal conditions, both the regulatory and coding regions contained the typically repressive H3K9me2 mark, which was lost after 30 min of water deprivation. As analogously conjectured for the paralogous gene Asr1, rapidly acquired new Asr2 epialleles in somatic cells due to desiccation might be stable enough and heritable through the germ line across generations, thereby efficiently contributing to constitutive, adaptive gene expression during the evolution of desiccation-tolerant populations or species.
Dekker, Alain D; De Deyn, Peter P; Rots, Marianne G
Down syndrome (DS) is the most common genetic intellectual disability, caused by the triplication of the human chromosome 21 (HSA21). Although this would theoretically lead to a 1.5 fold increase in gene transcription, transcript levels of many genes significantly deviate. Surprisingly, the underlying cause of this gene expression variation has been largely neglected so far. Epigenetic mechanisms, including DNA methylation and post-translational histone modifications, regulate gene expression and as such might play a crucial role in the development of the cognitive deficits in DS. Various overexpressed HSA21 proteins affect epigenetic mechanisms and DS individuals are thus likely to present epigenetic aberrations. Importantly, epigenetic marks are reversible, offering a huge therapeutic potential to alleviate or cure certain genetic deficits. Current epigenetic therapies are already used for cancer and epilepsy, and might provide novel possibilities for cognition-enhancing treatment in DS as well. To that end, this review discusses the still limited knowledge on epigenetics in DS and describes the potential of epigenetic therapies to reverse dysregulated gene expression.
Alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells. The changes of expression and activity of lipid metabolizing enzymes are directly regulated by the activity of oncogenic signals. The dependence of tumor cells on the dysregulated lipid metabolism suggests that proteins involved in this process are excellent chemotherapeutic targets for cancer treatment. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered lipid metabolic pathways in cancer cells. Further understanding of dysregulated lipid metabolism and its associated signaling pathways will help us to better design efficient cancer therapeutic strategy.
Kaushik, Prashant; Anderson, James T
Epigenetics, defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence has been shown to play an important role in the etiopathogenesis of obesity. Obesity is associated with extensive gene expression changes in tissues throughout the body. Epigenetics is emerging as perhaps the most important mechanism through which the lifestyle-choices we make can directly influence the genome. Considerable epidemiological, experimental and clinical data have been amassed showing that the risk of developing disease in later life is dependent on early life conditions, mainly operating within the normative range of developmental exposures. In addition to the 'maternal' interactions, there has been increasing interest in the epigenetic mechanisms through which 'paternal' influences on offspring development can be achieved. Nutrition, among many other environmental factors, is a key player that can induce epigenetic changes not only in the directly exposed organisms but also in subsequent generations through the transgenerational inheritance of epigenetic traits. 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. Fortunately, epigenetic phenomena are dynamic and rather quickly reversible with intensive lifestyle changes. This is a very promising and sustainable resolution to the obesity pandemic.
Hirschey, Matthew D.; DeBerardinis, Ralph J.; Diehl, Anna Mae E.; Drew, Janice E.; Frezza, Christian; Green, Michelle F.; Jones, Lee W.; Ko, Young H.; Le, Anne; Lea, Michael A.; Locasale, Jason W.; Longo, Valter D.; Lyssiotis, Costas A.; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P.; Pedersen, Peter L.; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Sivanand, Sharanya; Vander Heiden, Matthew G.; Wellen, Kathryn E.
Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where the dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results suggest that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. PMID:26454069
Dadomo, Harold; Grecucci, Alessandro; Giardini, Irene; Ugolini, Erika; Carmelita, Alessandro; Panzeri, Marta
The term emotional dysregulation refers to an impaired ability to regulate unwanted emotional states. Scientific evidence supports the idea that emotional dysregulation underlies several psychological disorders as, for example: personality disorders, bipolar disorder type II, interpersonal trauma, anxiety disorders, mood disorders and post-traumatic stress disorder. Emotional dysregulation may derive from early interpersonal traumas in childhood. These early traumatic events create a persiste...
Menger, Yannick; Bettscheider, Marc; Murgatroyd, Chris; Spengler, Dietmar
Sexual differentiation of the brain takes place during a perinatal-sensitive time window as a result of gonadal hormone-induced activational and organizational effects on neuronal substrates. Increasing evidence suggests that epigenetic mechanisms can contribute to the establishment and maintenance of some aspects of these processes, and that these epigenetic mechanisms may themselves be under the control of sex hormones. Epigenetic programming of neuroendocrine and behavioral phenotypes frequently occurs sex specifically, pointing to sex differences in brain epigenetics as a possible determinant. Understanding how sex-specific epigenomes and sex-biased responses to environmental cues contribute to the development of brain diseases might provide new insights for epigenetic therapy.
Verma, Ranjana; Xu, Xiufen; Jaiswal, Manoj K; Olsen, Cara; Mears, David; Caretti, Giuseppina; Galdzicki, Zygmunt
Tungsten-alloy has carcinogenic potential as demonstrated by cancer development in rats with intramuscular implanted tungsten-alloy pellets. This suggests a potential involvement of epigenetic events previously implicated as environmental triggers of cancer. Here, we tested metal induced cytotoxicity and epigenetic modifications including H3 acetylation, H3-Ser10 phosphorylation and H3-K4 trimethylation. We exposed human embryonic kidney (HEK293), human neuroepithelioma (SKNMC), and mouse myoblast (C2C12) cultures for 1-day and hippocampal primary neuronal cultures for 1-week to 50-200 μg/ml of tungsten-alloy (91% tungsten/6% nickel/3% cobalt), tungsten, nickel, and cobalt. We also examined the potential role of intracellular calcium in metal mediated histone modifications by addition of calcium channel blockers/chelators to the metal solutions. Tungsten and its alloy showed cytotoxicity at concentrations > 50 μg/ml, while we found significant toxicity with cobalt and nickel for most tested concentrations. Diverse cell-specific toxic effects were observed, with C2C12 being relatively resistant to tungsten-alloy mediated toxic impact. Tungsten-alloy, but not tungsten, caused almost complete dephosphorylation of H3-Ser10 in C2C12 and hippocampal primary neuronal cultures with H3-hypoacetylation in C2C12. Dramatic H3-Ser10 dephosphorylation was found in all cobalt treated cultures with a decrease in H3 pan-acetylation in C2C12, SKNMC and HEK293. Trimethylation of H3-K4 was not affected. Both tungsten-alloy and cobalt mediated H3-Ser10 dephosphorylation were reversed with BAPTA-AM, highlighting the role of intracellular calcium, confirmed with 2-photon calcium imaging. In summary, our results for the first time reveal epigenetic modifications triggered by tungsten-alloy exposure in C2C12 and hippocampal primary neuronal cultures suggesting the underlying synergistic effects of tungsten, nickel and cobalt mediated by changes in intracellular calcium homeostasis and
Sokolova, D A; Venzhen, G S; Kravets, A P
The hypothesis on connection between various germination rates of seeds that are not in dormancy with their epigenetic polymorphism has been checked. It was shown that seedlings which were characterized with different germination rates had different methylation patterns of transcribed and satellite DNA. Different cytogenetic characteristics and their changes were observed under UV-C irradiation as well.
BackgroundMelon (Cucumis melo) is an important vegetable crop from the Cucurbitaceae family and a reference model specie for sex determination, fruit ripening and vascular fluxes studies. Nevertheless, the nature and role of its epigenome in gene expression regulation and more specifically in sex determination remains largely unknown.ResultsWe have investigated genome wide H3K27me3 and H3K9ac histone modifications and gene expression dynamics, in five melon organs. H3K9ac and H3K27me3 were mainly distributed along gene-rich regions and constrained to gene bodies. H3K9ac was preferentially located at the TSS, whereas H3K27me3 distributed uniformly from TSS to TES. As observed in other species, H3K9ac and H3K27me3 correlated with high and low gene expression levels, respectively. Comparative analyses of unisexual flowers pointed out sex-specific epigenetic states of TFs involved in ethylene response and flower development. Chip-qPCR analysis of laser dissected carpel and stamina primordia, revealed sex-specific histone modification of MADS-box genes. Using sex transition mutants, we demonstrated that the female promoting gene, CmACS11, represses the expression of the male promoting gene CmWIP1 via deposition of H3K27me3.ConclusionsOur findings reveal the organ-specific landscapes of H3K9ac and H3K27me3 in melon. Our results also provide evidence that the sex determination genes recruit histone modifiers to orchestrate unisexual flower development in monoecious species.
Kilvitis, Holly J; Alvarez, Mariano; Foust, Christy M; Schrey, Aaron W; Robertson, Marta; Richards, Christina L
Biologists have assumed that heritable variation due to DNA sequence differences (i.e., genetic variation) allows populations of organisms to be both robust and adaptable to extreme environmental conditions. Natural selection acts on the variation among different genotypes and ultimately changes the genetic composition of the population. While there is compelling evidence about the importance of genetic polymorphisms, evidence is accumulating that epigenetic mechanisms (e.g., chromatin modifications, DNA methylation) can affect ecologically important traits, even in the absence of genetic variation. In this chapter, we review this evidence and discuss the consequences of epigenetic variation in natural populations. We begin by defining the term epigenetics, providing a brief overview of various epigenetic mechanisms, and noting the potential importance of epigenetics in the study of ecology. We continue with a review of the ecological epigenetics literature to demonstrate what is currently known about the amount and distribution of epigenetic variation in natural populations. Then, we consider the various ecological contexts in which epigenetics has proven particularly insightful and discuss the potential evolutionary consequences of epigenetic variation. Finally, we conclude with suggestions for future directions of ecological epigenetics research.
Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy developme...
Богданов, Алексей В; Гришко, Юлия М; Костенко, Виталий А
intake of inorganic nitrates is typically accompanied by production of excessive amount of nitric oxide (NO), which level is maintained by the mechanism of autoregulation known as the NO cycle. Hypothetically, this process may be disrupted with fluorides that are able to suppress arginase pathway of L-arginine metabolism, which competes with NO-synthase pathway. to study mechanisms of disregulation of oxidative (NO-synthase) and non-oxidative (arginase) metabolic pathways of L-arginine in the tissues of periodontium under combined excessive sodium nitrate and fluoride intake. these investigations were carried out on 90 white Wistar rats. Homogenates of parodontium soft tissues were used to assess spectrophotometrically the total activities of NO-synthase (NOS), arginase, ornithine decarboxylase as well as the peroxynitrite concentration. typical for the isolated sodium nitrate administration inhibition of total NOS activity varies under combined administration of nitrate and sodium fluoride and is usually manifested by its hyperactivation that is accompanied by an increase in peroxynitrite concentration. At this time arginase and ornithine decarboxylase activity is observed to be substantially reduced. The administration of aminoguanidine, an iNOS inhibitor, (20 mg/kg, twice a week during the experiment) increases arginase and ornithine decarboxylase activities, and the administration of L-arginine (500 mg/kg, twice a week) results in the increase of arginase activity. The administration of L-selenomethionine, a peroxynitrite scavenger (3 mg/kg, twice a week), and JSH-23 (4-methyl-N-(3-phenylpropyl) benzene-1,2-diamine, an inhibitor of NF-κB activation (1 mg/kg, twice a week) for modeling binary nitrate and fluoride intoxication reduces the total concentration of NOS activity and peroxynitrite concentration, and increases ornithine decarboxylase activity. the combined effect of nitrate and sodium fluoride for 30 days leads to disregulatory increased activity of NO
Le Bouc, Yves; Rossignol, Sylvie; Azzi, Salah; Brioude, Frédéric; Cabrol, Sylvie; Gicquel, Christine; Netchine, Irène
maternally methylated ICR2 region). The underlying cause of these imprinting defects, both spontaneous and ART-related, is unclear. However, recent data show that, in patients with BWS or RSS, including those conceived with the help of ART the DNA methylation defect involves imprinted loci other than 11p15. This suggests that unfaithful maintenance of DNA methylation marks following fertilization involves dysregulation of a trans-acting regulatory factor.
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...
Lori A. McEachern
Full Text Available Non-model organisms are generally more difficult and/or time consuming to work with than model organisms. In addition, epigenetic analysis of model organisms is facilitated by well-established protocols, and commercially-available reagents and kits that may not be available for, or previously tested on, non-model organisms. Given the evolutionary conservation and widespread nature of many epigenetic mechanisms, a powerful method to analyze epigenetic phenomena from non-model organisms would be to use transgenic model organisms containing an epigenetic region of interest from the non-model. Interestingly, while transgenic Drosophila and mice have provided significant insight into the molecular mechanisms and evolutionary conservation of the epigenetic processes that target epigenetic control regions in other model organisms, this method has so far been under-exploited for non-model organism epigenetic analysis. This paper details several experiments that have examined the epigenetic processes of genomic imprinting and paramutation, by transferring an epigenetic control region from one model organism to another. These cross-species experiments demonstrate that valuable insight into both the molecular mechanisms and evolutionary conservation of epigenetic processes may be obtained via transgenic experiments, which can then be used to guide further investigations and experiments in the species of interest.
van der Gun, B. T. F.; de Groote, M. L.; Kazemier, H. G.; Arendzen, A. J.; Terpstra, P.; Ruiters, M. H. J.; McLaughlin, P. M. J.; Rots, M. G.
BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is overexpressed on carcinomas, and its downregulation inhibits the oncogenic potential of multiple tumour types. Here, we investigated underlying mechanisms of epcam overexpression in ovarian carcinoma. METHODS: Expression of EpCAM and DNA m
De Planell-Saguer, Mariangels; Lovinsky-Desir, Stephanie; Miller, Rachel L.
Asthma is a complex disease with genetic and environmental influences and emerging evidence suggests that epigenetic regulation is also a major contributor. Here, we focus on the developing paradigm that epigenetic dysregulation in asthma and allergy may start as early as in utero following several environmental exposures. We summarize the pathways important to the allergic immune response that are epigenetically regulated, the key environmental exposures associated with epigenetic changes in...
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
Kuasne, Hellen; Marchi, Fabio Albuquerque; Rogatto, Silvia Regina
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 in diffe......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...... 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...... 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...
Shinjo, Keiko; Kondo, Yutaka
Recent studies provide compelling evidence that epigenetic dysregulation is involved in almost every step of tumor development and progression. Differences in tumor behavior, which ultimately reflects clinical outcome, can be explained by variations in gene expression patterns generated by epigenetic mechanisms, such as DNA methylation. Therefore, epigenetic abnormalities are considered potential biomarkers and therapeutic targets. DNA methylation is stable at certain specific loci in cancer cells and predominantly reflects the characteristic clinicopathological features. Thus, it is an ideal biomarker for cancer screening, classification and prognostic purposes. Epigenetic treatment for cancers is based on the pharmacologic targeting of various core transcriptional programs that sustains cancer cell identity. Therefore, targeting aberrant epigenetic modifiers may be effective for multiple processes compared with using a selective inhibitor of aberrant single signaling pathway. This review provides an overview of the epigenetic alterations in human cancers and discusses about novel therapeutic strategies targeting epigenetic alterations.
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, devel...
Wang, Chao; Yang, Qin; Wang, Weixiang; Li, Yipu; Guo, Yanling; Zhang, Dongfeng; Ma, Xuena; Song, Wei; Zhao, Jiuran; Xu, Mingliang
A major resistance quantitative trait locus, qRfg1, significantly enhances maize resistance to Gibberella stalk rot, a devastating disease caused by Fusarium graminearum. However, the underlying molecular mechanism remains unknown. We adopted a map-based cloning approach to identify the resistance gene at qRfg1 and examined the dynamic epigenetic changes during qRfg1-mediated maize resistance to the disease. A CCT domain-containing gene, ZmCCT, is the causal gene at the qRfg1 locus and a polymorphic CACTA-like transposable element (TE1) c. 2.4 kb upstream of ZmCCT is the genetic determinant of allelic variation. The non-TE1 ZmCCT allele is in a poised state, with predictive bivalent chromatin enriched for both repressive (H3K27me3/H3K9me3) and active (H3K4me3) histone marks. Upon pathogen challenge, this non-TE1 ZmCCT allele was promptly induced by a rapid yet transient reduction in H3K27me3/H3K9me3 and a progressive decrease in H3K4me3, leading to disease resistance. However, TE1 insertion in ZmCCT caused selective depletion of H3K4me3 and enrichment of methylated GC to suppress the pathogen-induced ZmCCT expression, resulting in disease susceptibility. Moreover, ZmCCT-mediated resistance to Gibberella stalk rot is not affected by photoperiod sensitivity. This chromatin-based regulatory mechanism enables ZmCCT to be more precise and timely in defense against F. graminearum infection. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.
Sun, Cong; Burgner, David P; Ponsonby, Anne-Louise; Saffery, Richard; Huang, Rae-Chi; Vuillermin, Peter J; Cheung, Michael; Craig, Jeffrey M
Cardiovascular disease (CVD) is the leading cause of death worldwide and originates in early life. The exact mechanisms of this early-life origin are unclear, but a likely mediator at the molecular level is epigenetic dysregulation of gene expression. Epigenetic factors have thus been posited as the likely drivers of early-life programming of adult-onset diseases. This review summarizes recent advances in epidemiology and epigenetic research of CVD risk in children, with a particular focus on twin studies. Classic twin studies enable partitioning of phenotypic variance within a population into additive genetic, shared, and nonshared environmental variances, and are invaluable in research in this area. Longitudinal cohort twin studies, in particular, may provide important insights into the role of epigenetics in the pathogenesis of CVD. We describe candidate gene and epigenome-wide association studies (EWASs) and transgenerational epigenetic inheritance of CVD, and discuss the potential for evidence-based interventions. Identifying epigenetic changes associated with CVD-risk biomarkers in children will provide new opportunities to unravel the underlying biological mechanism of the origins of CVD and enable identification of those at risk for early-life interventions to alter the risk trajectory and potentially reduce CVD incidence later in life.
He, Su-Yun; Lu, Sheng-Feng; Zhu, Bing-Mei
As an important content of alternative and complementary medicine, acupuncture therapy has been proved to be effective in relieving myocardial ischemia (MI). Authors of the present paper review recent progress of researches on acupuncture therapy in resisting MI from 1) improving cardiovascular function and promoting angiogenesis, and 2) protecting myocardial cells from further injury and reducing cellular apoptosis at different pathological stages of MI. Moreover, the authors discuss the characteristics of epigenetic regulation in the process of MI and cardiac repair including the methylating of DNA, modification of histone, remodeling of the chromatin, and micro-RNA expression, mediating cellular apoptosis, regeneration of myocardial blood vessels, etc. The authors hold that future studies on the underlying mechanisms of acupuncture therapy in the prevention and treatment of MI from epigenetics may be a new approach and a new direction.
Quadrana, Leandro; Colot, Vincent
Transgenerational epigenetics is defined in opposition to developmental epigenetics and implies an absence of resetting of epigenetic states between generations. Unlike mammals, plants appear to be particularly prone to this type of inheritance. In this review, we summarize our knowledge about transgenerational epigenetics in plants, which entails heritable changes in DNA methylation. We emphasize the role of transposable elements and other repeat sequences in the creation of epimutable alleles. We also argue that because reprogramming of DNA methylation across generations seems limited in plants, the inheritance of DNA methylation defects results from the failure to reinforce rather than reset this modification during sexual reproduction. We compare genome-wide assessments of heritable DNA methylation variation and its phenotypic impact in natural populations to those made using near-isogenic populations derived from crosses between parents with experimentally induced DNA methylation differences. Finally, we question the role of the environment in inducing transgenerational epigenetic variation and briefly present theoretical models under which epimutability is expected to be selected for.
Li, Guideng; Zan, Hong; Xu, Zhenming; Casali, Paolo
Epigenetic marks, such as DNA methylation, histone post-translational modifications and miRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR), and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and miRNAs modulate the expression of critical elements of that machinery, such as activation-induced cytidine deaminase (AID), as well as factors central to plasma cell differentiation, such as B lymphocyte-induced maturation protein-1 (Blimp-1). These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such as those targeted in autoimmunity, and B cell neoplasia.
Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.
Maternal nutrition at the time of conception and during pregnancy is considered a factor for individual differences in having obesity. The mechanisms underlying this association are likely partially epigenetic in nature, but pinning down the exact nature, location, and timing of these changes remain...
"Epigenetic transgenerational inheritance" (ETI) has been defined as germline (sperm or egg) transmission of epigenetic information between generations in the absence of direct exposures or genetic manipulations. Among reported cases of ETI in mammals, the majority are induced by environmental factors, including environmental toxicants [e.g. agricultural fungicide vinclozolin, plastic additive bisphenol A, pesticide methoxychlor, dioxin, di-(2-ethylhexyl) phthalate, dichlorodiphenyltrichloroethane, and hydrocarbons] and poor nutritional conditions. Although the ETI phenomenon is well established, the underlying mechanism remains elusive. Putative epimutations, including changes in DNA methylation and histone modification patterns, have been reported, but it remains unclear how these epimutations are formed in the first place, and how they are memorized in the germline and then get transmitted to subsequent generations. Based on recent advances in our understanding of regulatory noncoding RNAs (ncRNAs), I propose that ncRNAs are involved in ETI, during both the initial epimutation formation and the subsequent germline transmission of epimutations. ncRNAs can function at epigenetic levels by affecting DNA methylation and histone modifications, thereby changing gene transcriptional activities, which can lead to an altered mRNA transcriptome associated with a disease phenotype. Alternatively, novel or altered ncRNA expression can cause dysregulated post-transcriptional regulation, thus directly affecting the mRNA transcriptome and inducing a disease phenotype. Sperm-borne ncRNAs are potential mediators for epigenetic memory across generations, but they alone may not be sufficient for stable transmission of epimutations across generations. Overall, research on ncRNAs in the context of ETI is urgently needed to shed light on the underlying mechanism of ETI.
Williams, S D; Hughes, T E; Adler, C J; Brook, A H; Townsend, G C
In 2007, only four years after the completion of the Human Genome Project, the journal Science announced that epigenetics was the 'breakthrough of the year'. Time magazine placed it second in the top 10 discoveries of 2009. While our genetic code (i.e. our DNA) contains all of the information to produce the elements we require to function, our epigenetic code determines when and where genes in the genetic code are expressed. Without the epigenetic code, the genetic code is like an orchestra without a conductor. Although there is now a substantial amount of published research on epigenetics in medicine and biology, epigenetics in dental research is in its infancy. However, epigenetics promises to become increasingly relevant to dentistry because of the role it plays in gene expression during development and subsequently potentially influencing oral disease susceptibility. This paper provides a review of the field of epigenetics aimed specifically at oral health professionals. It defines epigenetics, addresses the underlying concepts and provides details about specific epigenetic molecular mechanisms. Further, we discuss some of the key areas where epigenetics is implicated, and review the literature on epigenetics research in dentistry, including its relevance to clinical disciplines. This review considers some implications of epigenetics for the future of dental practice, including a 'personalized medicine' approach to the management of common oral diseases.
Campbell, Robert M; Tummino, Peter J
Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved "first generation" of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area.
correspondence should be addressed. J. M. Denu, 2140 Wisconsin Institute for Discovery, 330 North Orchard Street, Madison, WI 53715, Phone: 608-265...tissue compartments. Epithelial staining intensity automatically quantified using inForm software was used for analysis of protein expression
El Hajj, Nady; Dittrich, Marcus; Böck, Julia; Kraus, Theo F. J.; Nanda, Indrajit; Müller, Tobias; Seidmann, Larissa; Tralau, Tim; Galetzka, Danuta; Schneider, Eberhard; Haaf, Thomas
ABSTRACT Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3–11 times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions. PMID:27245352
Shivendra D Shukla; Annayya R Aroor
Alcohol consumption causes cellular injury. Recent developments indicate that ethanol induces epigenetic alterations, particularly acetylation, methylation of histones, and hypo- and hypermethylation of DNA. This has opened up a new area of interest in ethanol research and is providing novel insight into actions of ethanol at the nucleosomal level in relation to gene expression and patho-physiological consequences. The epigenetic effects are mainly attributable to ethanol metabolic stress (Emess), generated by the oxidative and non-oxidative metabolism of ethanol, and dysregulation of methionine metabolism. Epigenetic changes are important in ethanol-induced hepatic steatosis, fibrosis, carcinoma and gastrointestinal injury. This editorial highlights these new advances and its future potential.
Martino, David; Kesper, Dörthe A; Amarasekera, Manori; Harb, Hani; Renz, Harald; Prescott, Susan
Epigenetic mechanisms such as DNA methylation, histone modification, and micro RNA signaling regulate the activity of the genome. Virtually all aspects of immunity involve some level of epigenetic regulation, whether it be host defense or in mediating tolerance. These processes are critically important in mediating dynamic responses to the environment over the life course of the individual, yet we are only just beginning to understand how dysregulation in these pathways may play a role in immune disease. Here, we give a brief chronological overview of epigenetic processes during immune development in health and disease.
Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.
Ahmadi, Majid; Gharibi, Tohid; Dolati, Sanam; Rostamzadeh, Davood; Aslani, Saeed; Baradaran, Behzad; Younesi, Vahid; Yousefi, Mehdi
Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. However, the precise etiology of autoimmune diseases remains largely unknown. Epigenetic mechanisms like alterations in the post-translational modification of histones and DNA methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. Recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. Epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. In this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations.
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.
Lubin, Farah D
Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.
Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease involving multiple organs and the presence of anti-nuclear antibodies. The pathogenesis of SLE has been intensively studied but remains far from clear. B and T lymphocyte abnormalities, dysregulation of apoptosis, defects in the clearance of apoptotic materials, and various genetic and epigenetic factors are attributed to the development of SLE. The latest research findings point to the association between abnormal epigenetic regulation and SLE, which has attracted considerable interest worldwide. It is the purpose of this review to present and discuss the relationship between aberrant epigenetic regulation and SLE, including DNA methylation, histone modifications and microRNAs in patients with SLE, the possible mechanisms of immune dysfunction caused by epigenetic changes, and to better understand the roles of aberrant epigenetic regulation in the initiation and development of SLE and to provide an insight into the related therapeutic options in SLE.
Full Text Available Thanks to the creative effort of Prof. Trygve O. Tollefsbol (Dept. of Biology, University of Alabama at Birmingham, USA we can handle the second edition in just seven years of this must needed volume devoted to the study of the epigenome. In the very same window-time the field of epigenetics is dramatically changed as for the technical tools employed by the pupils of this pervasive discipline: actually there is no one hot topics in biology (e.g., development, differentiation, genomic toxicity and medicine .....
Liu, Nian; Pan, Tao
Mammalian messenger and long non-coding RNA contain tens of thousands of post-transcriptional chemical modifications. Among these, the N6-methyl-adenosine (m6A) modification is the most abundant and can be removed by specific mammalian enzymes. M6A modification is recognized by families of RNA binding proteins that affect many aspects of mRNA function. mRNA/lncRNA modification represents another layer of epigenetic regulation of gene expression, analogous to DNA methylation and histone modifi...
Qureshi, Irfan A; Mehler, Mark F
The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging.
Full Text Available Raman Baweja, Susan D Mayes, Usman Hameed, James G Waxmonsky Department of Psychiatry, Penn State University College of Medicine, Hershey, PA, USA Abstract: Disruptive mood dysregulation disorder (DMDD was introduced as a new diagnostic entity under the category of depressive disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5. It was included in DSM-5 primarily to address concerns about the misdiagnosis and consequent overtreatment of bipolar disorder in children and adolescents. DMDD does provide a home for a large percentage of referred children with severe persistent irritability that did not fit well into any DSM, Fourth Edition (DSM-IV diagnostic category. However, it has been a controversial addition to the DSM-5 due to lack of published validity studies, leading to questions about its validity as a distinct disorder. In this article, the authors discuss the diagnostic criteria, assessment, epidemiology, criticism of the diagnosis, and pathophysiology, as well as treatment and future directions for DMDD. They also review the literature on severe mood dysregulation, as described by the National Institute of Mental Health, as the scientific support for DMDD is based primarily on studies of severe mood dysregulation. Keywords: disruptive mood dysregulation disorder, persistent irritability, temper outbursts
Full Text Available Poly(ADP-ribosepolymerase (Parp is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose chains (known as PARylation. Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.
Kagale, Sateesh; Rozwadowski, Kevin
Ethylene-responsive element binding factor-associated Amphiphilic Repression (EAR) motif-mediated transcriptional repression is emerging as one of the principal mechanisms of plant gene regulation. The EAR motif, defined by the consensus sequence patterns of either LxLxL or DLNxxP, is the most predominant form of transcriptional repression motif so far identified in plants. Additionally, this active repression motif is highly conserved in transcriptional regulators known to function as negative regulators in a broad range of developmental and physiological processes across evolutionarily diverse plant species. Recent discoveries of co-repressors interacting with EAR motifs, such as TOPLESS (TPL) and AtSAP18, have begun to unravel the mechanisms of EAR motif-mediated repression. The demonstration of genetic interaction between mutants of TPL and AtHDA19, co-complex formation between TPL-related 1 (TPR1) and AtHDA19, as well as direct physical interaction between AtSAP18 and AtHDA19 support a model where EAR repressors, via recruitment of chromatin remodeling factors, facilitate epigenetic regulation of gene expression. Here, we discuss the biological significance of EAR-mediated gene regulation in the broader context of plant biology and present literature evidence in support of a model for EAR motif-mediated repression via the recruitment and action of chromatin modifiers. Additionally, we discuss the possible influences of phosphorylation and ubiquitination on the function and turnover of EAR repressors.
Agenda Download the Workshop Agenda (PDF) The workshop included presentations and discussions by scientific experts pertaining to three topics (i.e., epigenetic changes associated with diverse stressors, key science considerations in understanding epigenetic changes, and practical application of epigenetic tools to address cumulative risks from environmental stressors), to address several questions under each topic, and included an opportunity for attendees to participate in break-out groups, provide comments and ask questions. Workshop Goals The workshop seeks to examine the opportunity for use of aggregate epigenetic change as an indicator in cumulative risk assessment for populations exposed to multiple stressors that affect epigenetic status. Epigenetic changes are specific molecular changes around DNA that alter expression of genes. Epigenetic changes include DNA methylation, formation of histone adducts, and changes in micro RNAs. Research today indicates that epigenetic changes are involved in many chronic diseases (cancer, cardiovascular disease, obesity, diabetes, mental health disorders, and asthma). Research has also linked a wide range of stressors including pollution and social factors with occurrence of epigenetic alterations. Epigenetic changes have the potential to reflect impacts of risk factors across multiple stages of life. Only recently receiving attention is the nexus between the factors of cumulative exposure to environmental
Context: Anorexia nervosa is a primary psychiatric disorder with serious endocrine consequences, including dysregulation of the gonadal, adrenal, and GH axes, and severe bone loss. This Update reviews recent advances in the understanding of the endocrine dysregulation observed in this state of chronic starvation, as well as the mechanisms underlying the disease itself. Evidence Acquisition: Findings of this update are based on a PubMed search and the author's knowledge of this field. Evidence Synthesis: Recent studies have provided insights into the mechanisms underlying endocrine dysregulation in states of chronic starvation as well as the etiology of anorexia nervosa itself. This includes a more complex understanding of the pathophysiologic bases of hypogonadism, hypercortisolemia, GH resistance, appetite regulation, and bone loss. Nevertheless, the etiology of the disease remains largely unknown, and effective therapies for the endocrine complications and for the disease itself are lacking. Conclusions: Despite significant progress in the field, further research is needed to elucidate the mechanisms underlying the development of anorexia nervosa and its endocrine complications. Such investigations promise to yield important advances in the therapeutic approach to this disease as well as to the understanding of the regulation of endocrine function, skeletal biology, and appetite regulation. PMID:21976742
Niller, Hans Helmut; Minarovits, Janos
In multicellular eukaryotes including plants, animals and humans, epigenetic reprogramming may play a role in the pathogenesis of a wide variety of diseases. Recent studies revealed that in addition to viruses, pathogenic bacteria are also capable to dysregulate the epigenetic machinery of their target cells. In this chapter we focus on epigenetic alterations induced by bacteria infecting humans. Most of them are obligate or facultative intracellular bacteria that produce either bacterial toxins and surface proteins targeting the host cell membrane, or synthesise effector proteins entering the host cell nucleus. These bacterial products typically elicit histone modifications, i.e. alter the "histone code". Bacterial pathogens are capable to induce alterations of host cell DNA methylation patterns, too. Such changes in the host cell epigenotype and gene expression pattern may hinder the antibacterial immune response and create favourable conditions for bacterial colonization, growth, or spread. Epigenetic dysregulation mediated by bacterial products may also facilitate the production of inflammatory cytokines and other inflammatory mediators affecting the epigenotype of their target cells. Such indirect epigenetic changes as well as direct interference with the epigenetic machinery of the host cells may contribute to the initiation and progression of malignant tumors associated with distinct bacterial infections.
Verhoeven, K.J.F.; Preite, V.
The role that epigenetic inheritance can play in adaptation may differ between sexuals and asexuals because (1) the dynamics of adaptation differ under sexual and asexual reproduction and the opportunities offered by epigenetic inheritance may affect these dynamics differently; and (2) in asexual re
Randi A. Phelps
Full Text Available Dysregulated fear, or the persistence of high levels of fear in low-threat contexts, is an early risk factor for the development of anxiety symptoms. Previous work has suggested both propensities for over-control and under-control of fearfulness as risk factors for anxiety problems, each of which may be relevant to observations of dysregulated fear. Given difficulty disentangling over-control and under-control through traditional behavioral measures, we used delta–beta coupling to begin to understand the degree to which dysregulated fear may reflect propensities for over- or under-control. We found that toddlers who showed high levels of dysregulated fear evidenced greater delta–beta coupling at frontal and central electrode sites as preschoolers relative to children who were low in dysregulated fear. Importantly, these differences were not observed when comparisons were made based on fear levels in high threat contexts. Results suggest dysregulated fear may involve tendencies toward over-control at the neural level.
Piletič, Klara; Kunej, Tanja
MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung's disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.
Herrera, Blanca M; Keildson, Sarah; Lindgren, Cecilia M
Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Herrera, Blanca M.; Keildson, Sarah; Lindgren, Cecilia M.
Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40–70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or “imprinting”, affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader–Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity. PMID:21466928
Quadrana, Leandro; Colot, Vincent
International audience; Transgenerational epigenetics is defined in opposition to developmental epi-genetics and implies an absence of resetting of epigenetic states between generations. Unlike mammals, plants appear to be particularly prone to this type of inheritance. In this review, we summarize our knowledge about trans-generational epigenetics in plants, which entails heritable changes in DNA methylation. We emphasize the role of transposable elements and other repeat sequences in the cr...
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.
Zheng, Shijie C; Widschwendter, Martin; Teschendorff, Andrew E
It is well-established that the DNA methylation landscape of normal cells undergoes a gradual modification with age, termed as 'epigenetic drift'. Here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. We propose a new terminology to help distinguish the different components of epigenetic drift, with the aim of clarifying the role of the epigenetic clock, mitotic clocks and active changes, which accumulate in response to environmental disease risk factors. We further highlight the growing evidence that epigenetic changes associated with cancer risk factors may play an important causal role in cancer development, and that monitoring these molecular changes in normal cells may offer novel risk prediction and disease prevention strategies.
Full Text Available Epigenetic changes, such as alteration of DNA methylation patterns, have been proposed as a molecular mechanism underlying the effect of alcohol on the maintenance of adult stem cells. We have performed genome-wide gene expression microarray and DNA methylome analysis to identify molecular alterations via DNA methylation changes associated with exposure of human dental pulp stem cells (DPSCs to ethanol (EtOH. By combined analysis of the gene expression and DNA methylation, we have found a significant number of genes that are potentially regulated by EtOH-induced DNA methylation. As a focused approach, we have also performed a pathway-focused RT-PCR array analysis to examine potential molecular effects of EtOH on genes involved in epigenetic chromatin modification enzymes, fibroblastic markers, and stress and toxicity pathways in DPSCs. We have identified and verified that lysine specific demethylase 6B (KDM6B was significantly dysregulated in DPSCs upon EtOH exposure. EtOH treatment during odontogenic/osteogenic differentiation of DPSCs suppressed the induction of KDM6B with alterations in the expression of differentiation markers. Knockdown of KDM6B resulted in a marked decrease in mineralization from implanted DPSCs in vivo. Furthermore, an ectopic expression of KDM6B in EtOH-treated DPSCs restored the expression of differentiation-related genes. Our study has demonstrated that EtOH-induced inhibition of KDM6B plays a role in the dysregulation of odontogenic/osteogenic differentiation in the DPSC model. This suggests a potential molecular mechanism for cellular insults of heavy alcohol consumption that can lead to decreased mineral deposition potentially associated with abnormalities in dental development and also osteopenia/osteoporosis, hallmark features of fetal alcohol spectrum disorders.
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.
Gupta, Chanchal; Kaur, Jasmine; Tikoo, Kulbhushan
Hyperglycemia is a critical risk factor for development and progression of breast cancer. We have recently reported that high glucose induces phosphorylation of histone H3 at Ser 10 as well as de-phosphorylation of GSK-3β at Ser 9 in MDA-MB-231 cells. Here, we elucidate the mechanism underlying hyperglycemia-induced proliferation in MDA-MB-231 breast cancer cells. We provide evidence that hyperglycemia led to increased DNA methylation and DNMT1 expression in MDA-MB-231 cells. High glucose condition led to significant increase in the expression of PCNA, cyclin D1 and decrease in the expression of PTPN 12, p21 and PTEN. It also induced hypermethylation of DNA at the promoter region of PTPN 12, whereas hypomethylation at Vimentin and Snail. Silencing of GSK-3β by siRNA prevented histone H3 phosphorylation and reduced DNMT1 expression. We show that chromatin obtained after immunoprecipitation with phospho-histone H3 was hypermethylated under high glucose condition, which indicates a cross-talk between DNA methylation and histone H3 phosphorylation. ChIP-qPCR analysis revealed up-regulation of DNMT1 and metastatic genes viz. Vimentin, Snail and MMP-7 by phospho-histone H3, which were down-regulated upon GSK-3β silencing. To the best of our knowledge, this is the first report which shows that interplay between GSK-3β activation, histone H3 phosphorylation and DNA methylation directs proliferation of breast cancer cells.
Gupta, Chanchal; Kaur, Jasmine; Tikoo, Kulbhushan, E-mail: email@example.com
Hyperglycemia is a critical risk factor for development and progression of breast cancer. We have recently reported that high glucose induces phosphorylation of histone H3 at Ser 10 as well as de-phosphorylation of GSK-3β at Ser 9 in MDA-MB-231 cells. Here, we elucidate the mechanism underlying hyperglycemia-induced proliferation in MDA-MB-231 breast cancer cells. We provide evidence that hyperglycemia led to increased DNA methylation and DNMT1 expression in MDA-MB-231 cells. High glucose condition led to significant increase in the expression of PCNA, cyclin D1 and decrease in the expression of PTPN 12, p21 and PTEN. It also induced hypermethylation of DNA at the promoter region of PTPN 12, whereas hypomethylation at Vimentin and Snail. Silencing of GSK-3β by siRNA prevented histone H3 phosphorylation and reduced DNMT1 expression. We show that chromatin obtained after immunoprecipitation with phospho-histone H3 was hypermethylated under high glucose condition, which indicates a cross-talk between DNA methylation and histone H3 phosphorylation. ChIP-qPCR analysis revealed up-regulation of DNMT1 and metastatic genes viz. Vimentin, Snail and MMP-7 by phospho-histone H3, which were down-regulated upon GSK-3β silencing. To the best of our knowledge, this is the first report which shows that interplay between GSK-3β activation, histone H3 phosphorylation and DNA methylation directs proliferation of breast cancer cells. - Highlights: • High glucose induces phosphorylation of histone H3 and dephosphorylation of GSK-3β. • Moreover, hyperglycemia also leads to increased DNA methylation in MDA-MB-231 cells. • Inhibition of GSK-3β prevented histone H3 phosphorylation and reduced DNMT1 levels. • Interplay exists between GSK-3β, histone H3 phosphorylation and DNA methylation.
Full Text Available The search for new approaches to treatment and prevention of heart failure is a major challenge in medicine. The adenosine triphosphate-sensitive potassium (KATP channel has been long associated with the ability to preserve myocardial function and viability under stress. High surface expression of membrane KATP channels ensures a rapid energy-sparing reduction in action potential duration (APD in response to metabolic challenges, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, thus sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force. In healthy hearts, calcium/calmodulin-dependent protein kinase II (CaMKII phosphorylates the Kir6.2 KATP channel subunit initiating a cascade responsible for KATP channel endocytosis. Here, activation of CaMKII in a transaortic banding (TAB model of heart failure is coupled with a 35-40% reduction in surface expression of KATP channels compared to hearts from sham-operated mice. Linkage between KATP channel expression and CaMKII is verified in isolated cardiomyocytes in which activation of CaMKII results in downregulation of KATP channel current. Accordingly, shortening of monophasic APD is slowed in response to hypoxia or heart rate acceleration in failing compared to non-failing hearts, a phenomenon previously shown to result in significant increases in oxygen consumption. Even in the absence of coronary artery disease, failing myocardium can be further injured by ischemia due to a mismatch between metabolic supply and demand. Ischemia-reperfusion injury, following ischemic preconditioning, is diminished in hearts with CaMKII inhibition compared to wild-type hearts and this advantage is largely eliminated when myocardial KATP channel expression is absent, supporting that the myocardial protective benefit of CaMKII inhibition in heart failure may be substantially mediated by KATP channels. Recognition of Ca
Nestor, Colm E; Ottaviano, Raffaele; Reinhardt, Diana; Cruickshanks, Hazel A; Mjoseng, Heidi K.; McPherson, Rhoanne C; Lentini, Antonio; Thomson, John P; Dunican, Donncha S; Pennings, Sari; Anderton, Stephen M.; Benson, Mikael; Meehan, Richard R
BackgroundThe DNA methylation profile of mammalian cell lines differs from the primary tissue from which they were derived, exhibiting increasing divergence from the in vivo methylation profile with extended time in culture. Few studies have directly examined the initial epigenetic and transcriptional consequences of adaptation of primary mammalian cells to culture, and the potential mechanisms through which this epigenetic dysregulation occurs is unknown.ResultsWe demonstrate that adaptation...
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.
McGuire, Joseph F; Small, Brent J; Lewin, Adam B; Murphy, Tanya K; De Nadai, Alessandro S; Phares, Vicky; Geffken, Gary; Storch, Eric A
Although obsessive compulsive disorder (OCD) and common co-occurring conditions share deficits in self-regulatory abilities, there has been minimal examination of impaired self-regulation (dysregulation) in youth with OCD. This study examined the association of dysregulation with symptom severity, impairment, and treatment outcome in pediatric OCD. Clinicians assessed obsessive-compulsive severity, family accommodation and global severity in 144 youth with OCD. Youth completed self-report severity ratings of anxiety and depressive symptoms. Parents completed the Child Behavior Checklist (CBCL), and both children and parents completed parallel ratings of obsessive-compulsive impairment. Ninety-seven youth received cognitive behavioral therapy (CBT) and were re-assessed after treatment. Dysregulation was assessed using the CBCL-Dysregulation Profile. Before treatment, dysregulated youth exhibited greater obsessive-compulsive symptom severity, depressive mood, family accommodation, and impairment than non-dysregulated youth. The magnitude of dysregulation directly predicted child-rated impairment, parent-rated impairment, and family accommodation, beyond obsessive-compulsive severity. The magnitude of pretreatment dysregulation predicted treatment discontinuation but not treatment response. Obsessive-compulsive symptom severity and dysregulation level significantly decreased after CBT. Dysregulated youth with OCD presented as more clinically severe than their non-dysregulated counterparts, and may require more individualized interventions to reduce dysregulated behavior to prevent CBT attrition. For treatment completers, CBT was associated with a decrease in dysregulation level.
Full Text Available Males and females responses to gestational overnutrition set the stage for subsequent sex-specific differences in adult onset non communicable diseases. Placenta, as a widely recognized programming agent, contibutes to the underlying processes. According to our previous findings, a high-fat diet during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes. We further investigated the impact of diet and sex on placental histology, transcriptomic and epigenetic signatures in mice. Both basal gene expression and response to maternal high-fat diet were sexually dimorphic in whole placentas. Numerous genes showed sexually dimorphic expression, but only 11 genes regardless of the diet. In line with the key role of genes belonging to the sex chromosomes, 3 of these genes were Y-specific and 3 were X-specific. Amongst all the genes that were differentially expressed under a high-fat diet, only 16 genes were consistently affected in both males and females. The differences were not only quantitative but remarkably qualitative. The biological functions and networks of genes dysregulated differed markedly between the sexes. Seven genes of the epigenetic machinery were dysregulated, due to effects of diet, sex or both, including the Y- and X-linked histone demethylase paralogues Kdm5c and Kdm5d, which could mark differently male and female epigenomes. The DNA methyltransferase cofactor Dnmt3l gene expression was affected, reminiscent of our previous observation of changes in global DNA methylation. Overall, this striking sexual dimorphism of programming trajectories impose a considerable revision of the current dietary interventions protocols.
Kobow, Katja; Blümcke, Ingmar
In humans, genomic DNA is organized in 23 chromosome pairs coding for roughly 25,000 genes. Not all of them are active at all times. During development, a broad range of different cell types needs to be generated in a highly ordered and reproducible manner, requiring selective gene expression programs. Epigenetics can be regarded as the information management system that is able to index or bookmark distinct regions in our genome to regulate the readout of DNA. It further comprises the molecular memory of any given cell, allowing it to store information of previously experienced external (e.g., environmental) or internal (e.g., developmental) stimuli, to learn from this experience and to respond. The underlying epigenetic mechanisms can be synergistic, antagonistic, or mutually exclusive and their large variety combined with the variability and interdependence is thought to provide the molecular basis for any phenotypic variation in physiological and pathological conditions. Thus, widespread reconfiguration of the epigenome is not only a key feature of neurodevelopment, brain maturation, and adult brain function but also disease.
Bai, Alfa H C; Wu, William K K; Xu, Liangliang; Wong, Sunny H; Go, Minnie Y; Chan, Anthony W H; Harbord, Marcus; Zhang, Shenghong; Chen, Minhu; Wu, Justin C Y; Chan, Michael W Y; Chan, Matthew T V; Chan, Francis K L; Sung, Joseph J Y; Yu, Jun; Cheng, Alfred S L; Ng, Siew C
Accumulating evidence supports epigenetic modifications in mediating intestinal immunity in inflammatory bowel disease [IBD] pathogenesis. This study aimed to identify key dysregulated epigenetic modulators and the molecular downstream pathways in IBD. Expression of 116 well-defined epigenetic modulators was profiled and validated in 96 intestinal tissues from patients with Crohn's disease [CD], ulcerative colitis [UC], and healthy controls using quantitative reverse transcriptase polymerase chain reaction [QRT-PCR], western blot, and immunohistochemistry. Dysregulation of histone modifications and IBD-related cytokines were examined by chromatin immunoprecipitation, luciferase activity, and gene expression analyses in normal colonic epithelial cell line, NCM460, upon small-molecule inhibition or RNA interference, followed by validation in primary colonic tissues. Targeted expression profiling uncovered seven differentially expressed epigenetic modulators, of which the down-regulation of lysine acetyltransferase 2B [KAT2B] mRNA and protein was the most significant and was consequently validated in inflamed CD and UC compared with healthy colonic tissues. KAT2B protein localised abundantly in nuclei of normal colonic epithelium but diminished in paired inflamed CD and UC tissues. Pharmacological inhibition of KAT2B by anacardic acid in NCM460 cells reduced the levels of histone H4 lysine 5 acetylation [H4K5ac] and interleukin-10 [IL-10] in a dose-dependent manner. Knockdown of KAT2B reduced the IL-10 promoter occupancy of KAT2B and H4K5ac, resulting in transcriptional silencing. IL-10 level was also diminished in inflamed IBD tissues. Our findings demonstrated a novel epigenetic mechanism of IL-10 dysregulation in IBD. Down-regulation of KAT2B may disrupt the innate and adaptive inflammatory responses due to the suppression of this crucial anti-inflammatory cytokine. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University
Full Text Available Emerging lines of research suggest that both testosterone and maladaptive reward processing can modulate behavioral dysregulation. Yet to date, no integrative account has been provided that systematically explains neuroendocrine function, dysregulation of reward, and behavioral dysregulation in a unified perspective. This is particularly important given specific neuroendocrine systems are potential mechanisms underlying and giving rise to reward-relevant behaviors. In this review, we propose a forward thinking approach to study the mechanisms of reward and behavioral dysregulation from a positive affective neuroendocrinology (PANE perspective. This approach holds that testosterone increases reward processing, which increases the likelihood of behavioral dysregulation. Additionally, the PANE framework holds that reward processing mediates the effects of testosterone on behavioral dysregulation. We also explore sources of potential sex differences and the roles of age, cortisol, and individual differences within the PANE framework. Finally, we discuss future prospects for research questions and methodology in the emerging field of affective neuroendocrinology.
Dadomo, Harold; Grecucci, Alessandro; Giardini, Irene; Ugolini, Erika; Carmelita, Alessandro; Panzeri, Marta
The term emotional dysregulation refers to an impaired ability to regulate unwanted emotional states. Scientific evidence supports the idea that emotional dysregulation underlies several psychological disorders as, for example: personality disorders, bipolar disorder type II, interpersonal trauma, anxiety disorders, mood disorders and post-traumatic stress disorder. Emotional dysregulation may derive from early interpersonal traumas in childhood. These early traumatic events create a persistent sensitization of the central nervous system in relation to early life stressing events. For this reason, some authors suggest a common endophenotypical origin across psychopathologies. In the last 20 years, cognitive behavioral therapy has increasingly adopted an interactive-ontogenetic view to explain the development of disorders associated to emotional dysregulation. Unfortunately, standard Cognitive Behavior Therapy (CBT) methods are not useful in treating emotional dysregulation. A CBT-derived new approach called Schema Therapy (ST), that integrates theory and techniques from psychodynamic and emotion focused therapy, holds the promise to fill this gap in cognitive literature. In this model, psychopathology is viewed as the interaction between the innate temperament of the child and the early experiences of deprivation or frustration of the subject's basic needs. This deprivation may lead to develop early maladaptive schemas (EMS), and maladaptive Modes. In the present paper we point out that EMSs and Modes are associated with either dysregulated emotions or with dysregulatory strategies that produce and maintain problematic emotional responses. Thanks to a special focus on the therapeutic relationship and emotion focused-experiential techniques, this approach successfully treats severe emotional dysregulation. In this paper, we make several comparisons between the main ideas of ST and the science of emotion regulation, and we present how to conceptualize pathological
Sarma eRajeev Kumar
Full Text Available Epigenetic silencing is a natural phenomenon in which the expression of gene is regulated through modifications of DNA, RNA or histone proteins. It is a mechanism for defending host genomes against the effects of transposable element, viral infection and acts as a modulator of expression of duplicated gene family members and as a silencer of transgenes. A major breakthrough in understanding the mechanism of epigenetic silencing was discovery of silencing in transgenic tobacco plants due to interaction between two homologous promoters. The molecular mechanism of epigenetic mechanism is highly complicated and it is not completely understood yet. Two different molecular routes have been proposed for this, i.e. transcriptional gene silencing (TGS, which is associated with heavy methylation of promoter regions and blocks the transcription of transgene. The basic mechanism underlying post-transcriptional gene silencing (PTGS is degradation of the cytosolic mRNA of transgenes or endogenous genes. Undesired transgene silencing is of a major concern in transgenic technology used in crop improvement. A complete understanding of this phenomenon will be very useful for transgenic applications, where silencing of specific genes are required. The current status of epigenetic silencing in transgenic technology has been discussed and summarized in this mini-review.
Campión, J; Milagro, F I; Martínez, J A
Excessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity-related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow-up its progress, as well as to research and develop newer therapeutic approaches.
Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao
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. PMID:27695375
Common DNA sequence variants inadequately explain variability in fat mass among individuals. Abnormal body weights are characteristic of specific imprinted-gene disorders. However, the relevance of imprinted genes to our understanding of obesity among the general population is uncertain. Hitherto unidentified imprinted genes and epigenetic mosaicism are two of the challenges for this emerging field of epigenetics. Subtle epigenetic differences in imprinted genes and gene networks are likely t...
Full Text Available Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.
Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.
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.
Pal, Sangita; Tyler, Jessica K
Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.
Neureiter, Daniel; Jäger, Tarkan; Ocker, Matthias; Kiesslich, Tobias
An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16(ink4a), are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.
Nielsen, David A.; Utrankar, Amol; Reyes, Jennifer A; Simons, Daniel D; Kosten, Thomas R.
Drug addiction continues to be a serious medical and social problem. Vulnerability to develop an addiction to drugs is dependent on genetic, environmental, social and biological factors. In particular, the interactions of environmental and genetic factors indicate the significance of epigenetic mechanisms, which have been found to occur in response to illicit drug use or as underlying factors in chronic substance abuse and relapse. Epigenetics is defined as the heritable and possibly reversib...
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.
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
This review considers the hypothesis that nutrition during infancy affects developmental epigenetics in the gut, causing metabolic imprinting of gastrointestinal (GI) structure and function. Fundamentals of epigenetic gene regulation are reviewed, with an emphasis on the epigenetic mechanism of DNA ...
Pilsner, J Richard; Parker, Mikhail; Sergeyev, Oleg; Suvorov, Alexander
Dioxins are a group of highly persistent chemicals that are generated as by-products of industrial and natural processes. Reduction in sperm counts is among the most sensitive endpoints of dioxin toxicity. The exact mechanism by which dioxins reduce sperm counts is not known. Recent data implicate the role of epididymal factors rather than disruption of spermatogenesis. Studies reviewed here demonstrate that dioxins induce the transfer of environmental conditions to the next generation via male germline following exposures during the window of epigenetic reprogramming of primordial germ cells. Increased incidence of birth defects in offspring of male veterans exposed to dioxin containing, Agent Orange, suggest that dioxins may induce epigenomic changes in male germ cells of adults during spermatogenesis. This is supported by recent animal data that show that environmental conditions can cause epigenetic dysregulation in sperm in the context of specific windows of epigenetic reprogramming during spermatogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.
Winters, Jason; Christoff, Kalina; Gorzalka, Boris B
The literature on dysregulated sexuality, whether theoretical, clinical or empirical, has failed to differentiate the construct from high sexual desire. In this study, we tested three hypotheses which addressed this issue. A sample of 6458 men and 7938 women, some of whom had sought treatment for sexual compulsivity, addiction or impulsivity, completed an online survey comprised of various sexuality measures. Men and women who reported having sought treatment scored significantly higher on measures of dysregulated sexuality and sexual desire. For men, women, and those who had sought treatment, dysregulated sexuality was associated with increased sexual desire. Confirmatory factor analysis supported a one-factor model, indicating that, in both male and female participants, dysregulated sexuality and sexual desire variables loaded onto a single underlying factor. The results of this study suggest that dysregulated sexuality, as currently conceptualized, labelled, and measured, may simply be a marker of high sexual desire and the distress associated with managing a high degree of sexual thoughts, feelings, and needs.
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.
Morgan L Kleiber
Full Text Available There is abundant evidence that prenatal alcohol exposure leads to a range of behavioural and cognitive impairments, categorized under the term fetal alcohol spectrum disorders (FASDs. These disorders are pervasive in Western cultures and represent the most common preventable source of neurodevelopmental disabilities. The genetic and epigenetic etiology of these phenotypes, including those factors that may maintain these phenotypes throughout the lifetime of an affected individual, has become a recent topic of investigation. This review integrates recent data that has progressed our understanding FASD as a continuum of molecular events, beginning with cellular stress response and ending with a long-term ‘footprint’ of epigenetic dysregulation across the genome. It reports on data from multiple ethanol-treatment paradigms in mouse models that identify changes in gene expression that occur with respect to neurodevelopmental timing of exposure and ethanol dose. These studies have identified patterns of genomic alteration that are dependent on the biological processes occurring at the time of ethanol exposure. This review also adds to evidence that epigenetic processes such as DNA methylation, histone modifications, and non-coding RNA regulation may underlie long-term changes to gene expression patterns. These may be initiated by ethanol-induced alterations to DNA and histone methylation, particularly in imprinted regions of the genome, affecting transcription which is further fine-tuned by altered microRNA expression. These processes are likely complex, genome-wide, and interrelated. The proposed model suggests a potential for intervention, given that epigenetic changes are malleable and may be altered by postnatal environment. This review accentuates the value of mouse models in deciphering the molecular etiology of FASD, including those processes that may provide a target for the ammelioration of this common yet entirely preventable disorder.
Zhan, Yi; Guo, Yu; Lu, Qianjin
Great progress has been made in the last decades in understanding the complex immune dysregulation in systemic lupus erythematosus (SLE), yet the efforts to pursue an effective treatment of SLE proved to be futile. The pathoetiology of SLE involves extremely complicated and multifactorial interaction among various genetic and epigenetic factors. Multiple gene loci predispose to disease susceptibility, and the interaction with epigenetic modifications mediated through sex, hormones, and the hypothalamo-pituitary-adrenal axis complicates susceptibility and manifestations of this disease. Finally, certain environmental and psychological factors probably trigger the disease via epigenetic mechanisms. In this review, we summarize and discuss recent epigenetic studies of SLE and suggest a personalized approach to the dissection of disease onset and therapy or precision medicine. We speculate that in the future, precision medicine based on epigenetic and genetic information could help guide more effective targeted therapeutic intervention. © 2016 S. Karger AG, Basel.
Janjigian, Yelena Y; Kelsen, David P
Gastric cancer is among the most common human malignancies and the second leading cause of cancer-related death. The different epidemiologic and histopathology of subtypes of gastric cancer are associated with different genomic patterns. Data suggests that gene expression patterns of proximal, distal gastric cancers-intestinal type, and diffuse/signet cell are well separated. This review summarizes the genetic and epigenetic changes thought to drive gastric cancer and the emerging paradigm of gastric cancer as three unique disease subtypes.
Full Text Available Epigenetic information can be passed on from one generation to another via DNA methylation, histone modifications and changes in small RNAs, a process called epigenetic memory. During a mammal’s lifecycle epigenetic reprogramming, or the resetting of most epigenetic marks, occurs twice. The first instance of reprogramming occurs in primordial germ cells and the second occurs following fertilization. These processes may be both passive and active. In order for epigenetic inheritance to occur the epigenetic modifications must be able to escape reprogramming. There are several examples supporting this non-Mendelian mechanism of inheritance including the prepacking of early developmental genes in histones instead of protamines in sperm, genomic imprinting via methylation marks, the retention of CenH3 in mammalian sperm and the inheritance of piwi-associated interfering RNAs. The ability of mammals to pass on epigenetic information to their progeny provides clear evidence that inheritance is not restricted to DNA sequence and epigenetics plays a key role in producing viable offspring.
Borrelli, Emiliana; Nestler, Eric J.; Allis, C. David; Sassone-Corsi, Paolo
Neurons are submitted to an exceptional variety of stimuli and are able to convert these into high-order functions, such as storing memories, controlling behavior, and governing consciousness. These unique properties are based on the highly flexible nature of neurons, a characteristic that can be regulated by the complex molecular machinery that controls gene expression. Epigenetic control, which largely involves events of chromatin remodeling, appears to be one way in which transcriptional regulation of gene expression can be modified in neurons. This review will focus on how epigenetic control in the mature nervous system may guide dynamic plasticity processes and long-lasting cellular neuronal responses. We outline the molecular pathways underlying chromatin transitions, propose the presence of an “epigenetic indexing code,” and discuss how central findings accumulating at an exponential pace in the field of epigenetics are conceptually changing our perspective of adult brain function. PMID:19109904
Bierne, Hélène; Hamon, Mélanie; Cossart, Pascale
Epigenetic mechanisms regulate expression of the genome to generate various cell types during development or orchestrate cellular responses to external stimuli. Recent studies highlight that bacteria can affect the chromatin structure and transcriptional program of host cells by influencing diverse epigenetic factors (i.e., histone modifications, DNA methylation, chromatin-associated complexes, noncoding RNAs, and RNA splicing factors). In this article, we first review the molecular bases of the epigenetic language and then describe the current state of research regarding how bacteria can alter epigenetic marks and machineries. Bacterial-induced epigenetic deregulations may affect host cell function either to promote host defense or to allow pathogen persistence. Thus, pathogenic bacteria can be considered as potential epimutagens able to reshape the epigenome. Their effects might generate specific, long-lasting imprints on host cells, leading to a memory of infection that influences immunity and might be at the origin of unexplained diseases.
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 e......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...
Falahi, Fahimeh; van Kruchten, Michel; Martinet, Nadine; Hospers, Geke A P; Rots, Marianne G
DNA methylation and histone modifications are important epigenetic modifications associated with gene (dys)regulation. The epigenetic modifications are balanced by epigenetic enzymes, so-called writers and erasers, such as DNA (de)methylases and histone (de)acetylases. Aberrant epigenetic alterations have been associated with various diseases, including breast cancer. Since aberrant epigenetic modifications are potentially reversible, they might represent targets for breast cancer therapy. Indeed, several drugs have been designed to inhibit epigenetic enzymes (epi-drugs), thereby reversing epigenetic modifications. US Food and Drug Administration approval has been obtained for some epi-drugs for hematological malignancies. However, these drugs have had very modest anti-tumor efficacy in phase I and II clinical trials in breast cancer patients as monotherapy. Therefore, current clinical trials focus on the combination of epi-drugs with other therapies to enhance or restore the sensitivity to such therapies. This approach has yielded some promising results in early phase II trials. The disadvantage of epi-drugs, however, is genome-wide effects, which may cause unwanted upregulation of, for example, pro-metastatic genes. Development of gene-targeted epigenetic modifications (epigenetic editing) in breast cancer can provide a novel approach to prevent such unwanted events. In this context, identification of crucial epigenetic modifications regulating key genes in breast cancer is of critical importance. In this review, we first describe aberrant DNA methylation and histone modifications as two important classes of epigenetic mutations in breast cancer. Then we focus on the preclinical and clinical epigenetic-based therapies currently being explored for breast cancer. Finally, we describe epigenetic editing as a promising new approach for possible applications towards more targeted breast cancer treatment.
AWARD NUMBER: WSlXWH-14-1-0230 TITLE: Identifying Epigenetic Modulators of Resistance to ERK Signaling Inhibitors PRINCIPAL INVESTIGATOR: Emily...5a. CONTRACT NUMBER Identifying Epigenetic Modulators of Resistance to ERK Signaling Inhibitors 5b. GRANT NUMBER W8 1XWH- 1 4 - 1 - 0230 5c...response to targeted therapies in cancer. However, a global and unbiased approach to decipher the epigenetic mechanisms underlying melanoma drug
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.
Preite, V.; Snoek, L.B.; Oplaat, C.; Biere, A.; Putten, van der W.H.; Verhoeven, K.J.F.
Epigenetic modifications, such as DNA methylation variation, can generate heritable phenotypic variation independent of the underlying genetic code. However, epigenetic variation in natural plant populations is poorly documented and little understood. Here, we test if northward range expansion of ob
Heyward, Frankie D; Gilliam, Daniel; Coleman, Mark A; Gavin, Cristin F; Wang, Jing; Kaas, Garrett; Trieu, Richard; Lewis, John; Moulden, Jerome; Sweatt, J David
Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus. Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic
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
Narita, Minoru; Watanabe, Moe; Hamada, Yusuke; Tamura, Hideki; Ikegami, Daigo; Kuzumaki, Naoko; Igarashi, Katsuhide
Genetic factors are involved in determinants for the risk of psychiatric disorders, and neurological and neurodegenerative diseases. Chronic pain stimuli and intense pain have effects at a cellular and/or gene expression level, and will eventually induce "cellular memory due to pain", which means that tissue damage, even if only transient, can elicit epigenetically abnormal transcription/translation and post-translational modification in related cells depending on the degree or kind of injury or associated conditions. Such cell memory/transformation due to pain can cause an abnormality in a fundamental intracellular response, such as a change in the three-dimensional structure of DNA, transcription, or translation. On the other hand, pain is a multidimensional experience with sensory-discriminative and motivational-affective components. Recent human brain imaging studies have examined differences in activity in the nucleus accumbens between controls and patients with chronic pain, and have revealed that the nucleus accumbens plays a role in predicting the value of a noxious stimulus and its offset, and in the consequent changes in the motivational state. In this review, we provide a very brief overview of a comprehensive understanding of chronic pain associated with emotional dysregulation due to transcriptional regulation, epigenetic modification and miRNA regulation.
Lau, Pierre; de Strooper, Bart
The complexity of the nervous system arises in part, from the large diversity of neural cell types that support the architecture of neuronal circuits. Recent studies have highlighted microRNAs as important players in regulating gene expression at the post-transcriptional level and therefore the phenotype of neural cells. A link between microRNAs and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease is becoming increasingly evident. Here, we discuss microRNAs in neurodegeneration, from the fruit fly and mouse utilized as experimental models to dysregulated microRNAs in human neurodegenerative disorders. We propose that studying microRNAs and their mRNA targets in the context of neurodegeneration will significantly contribute to the identification of proteins important for neuronal function and might reveal underlying molecular networks that drive these diseases.
Meloni, Maurizio; Testa, Giuseppe
Epigenetics is one of the most rapidly expanding fields in the life sciences. Its rise is frequently framed as a revolutionary turn that heralds a new epoch both for gene-based epistemology and for the wider discourse on life that pervades knowledge-intensive societies of the molecular age. The fundamentals of this revolution remain however to be scrutinized, and indeed the very contours of what counts as ‘epigenetic' are often blurred. This is reflected also in the mounting discourse on the societal implications of epigenetics, in which vast expectations coexist with significant uncertainty about what aspects of this science are most relevant for politics or policy alike. This is therefore a suitable time to reflect on the directions that social theory could most productively take in the scrutiny of this revolution. Here we take this opportunity in both its scholarly and normative dimension, that is, proposing a roadmap for social theorizing on epigenetics that does not shy away from, and indeed hopefully guides, the framing of its most socially relevant outputs. To this end, we start with an epistemological reappraisal of epigenetic discourse that valorizes the blurring of meanings as a critical asset for the field and privileged analytical entry point. We then propose three paths of investigation. The first looks at the structuring elements of controversies and visions around epigenetics. The second probes the mutual constitution between the epigenetic reordering of living phenomena and the normative settlements that orient individual and collective responsibilities. The third highlights the material import of epigenetics and the molecularization of culture that it mediates. We suggest that these complementary strands provide both an epistemically and socially self-reflective framework to advance the study of epigenetics as a molecular juncture between nature and nurture and thus as the new critical frontier in the social studies of the life sciences. PMID
Pennington, Katie L.; DeAngelis, Margaret M.
Degenerative retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy, have complex etiologies with environmental, genetic, and epigenetic contributions to disease pathology. Much effort has gone into elucidating both the genetic and the environmental risk factors for these retinal diseases. However, little is known about how these genetic and environmental risk factors bring about molecular changes that lead to pathology. Epigenetic mechanisms have received extensive attention of late for their promise of bridging the gap between environmental exposures and disease development via their influence on gene expression. Recent studies have identified epigenetic changes that associate with the incidence and/or progression of each of these retinal diseases. Therefore, these epigenetic modifications may be involved in the underlying pathological mechanisms leading to blindness. Further genome-wide epigenetic studies that incorporate well-characterized tissue samples, consider challenges similar to those relevant to gene expression studies, and combine the genome-wide epigenetic data with genome-wide genetic and expression data to identify additional potentially causative agents of disease are needed. Such studies will allow researchers to create much-needed therapeutics to prevent and/or intervene in disease progression. Improved therapeutics will greatly enhance the quality of life and reduce the burden of disease management for millions of patients living with these potentially blinding conditions. PMID:26966390
Wenzel, Dirk; Palladino, Francesca; Jedrusik-Bode, Monika
Epigenetics is defined as the study of heritable changes in gene expression that are not accompanied by changes in the DNA sequence. Epigenetic mechanisms include histone post-translational modifications, histone variant incorporation, non-coding RNAs, and nucleosome remodeling and exchange. In addition, the functional compartmentalization of the nucleus also contributes to epigenetic regulation of gene expression. Studies on the molecular mechanisms underlying epigenetic phenomena and their biological function have relied on various model systems, including yeast, plants, flies, and cultured mammalian cells. Here we will expose the reader to the current understanding of epigenetic regulation in the roundworm C. elegans. We will review recent models of nuclear organization and its impact on gene expression, the biological role of enzymes modifying core histones, and the function of chromatin-associated factors, with special emphasis on Polycomb (PcG) and Trithorax (Trx-G) group proteins. We will discuss how the C. elegans model has provided novel insight into mechanisms of epigenetic regulation as well as suggest directions for future research.
Feil, R.; Constancia, M.; Fraga, M.; Junien, C.; Carel, J.-C.; Boileau, P.; Le Bouc, Y.; Deal, C. L.; Lillycrop, K.; Scharfmann, R.; Sheppard, A.; Skinner, M.; Szyf, M.; Waterland, R. A.; Waxman, D. J.; Whitelaw, E.; Ong, K.; Albertsson-Wikland, K.
Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs. PMID:20971919
Mariman, E C M
Epigenetic phenomena are changes in phenotype that are due to resetting of gene expression under the influence of the environment or genetic factors without changing the DNA sequence. Usually this resetting occurs at a certain stage in life and remains fixed thereafter. In humans, evidence for epigenetic involvement in diet-related complex traits and disorders is accumulating. The fetal origins theory indicates that nutrition can influence the later life risk for certain common disorders like the metabolic syndrome. In parent-of-origin effects, the risk for a common disorder like type I diabetes depends on the sex of the parent who transmits genetic risk factors. Interestingly, both dietary and genetic factors can exert their epigenetic influence over several generations. Imprinting, i.e. silencing of one copy of an autosomal pair of genes, can be part of the mechanism pointing to the importance of DNA methylation. In addition, chromatin modifications have been shown to be involved in epigenetic manifestations. The intriguing possibility that diet may influence the direction and extent of epigenetic changes opens new ways for prevention or treatment of common disorders. At the same time, maternal nutrition might be used to actively direct fetal development with consequences for later life performance such as cognitive abilities. More knowledge on those novel applications is needed. This will in part come from novel strategies to map the epigenomic regions, allowing the identification of more genes involved in epigenetics and allowing the study of their response to nutrition.
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...
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...
Eric J Nestler
Full Text Available There has been increasing interest in the possibility that behavioral experience--in particular, exposure to stress--can be passed on to subsequent generations through heritable epigenetic modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. This Perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility--and the experimental evidence for and against the existence of such mechanisms--and outlines steps required for future investigations.
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.
Ribich, Scott; Harvey, Darren; Copeland, Robert A
Comprehensive whole-exome sequencing, DNA copy-number determination, and transcriptomic analyses of diverse cancers have greatly expanded our understanding of the biology of many tumor types. In addition to mutations in the common cell-of-origin specific driver mutations, these studies have also revealed a large number of loss-of-function and gain-of-function mutations in chromatin-modifying proteins (CMPs). This has revealed that epigenetic dysregulation is a common feature of most pediatric and adult cancers. Many specific and potent inhibitors have been developed for multiple CMP classes, which have assisted in elucidating the role of epigenetics as well as epigenetic vulnerabilities in these cancer types. Clinical trials with numerous CMP inhibitors are also currently in progress to evaluate the therapeutic potential of epigenetic inhibitors. In this review, we aim to provide a summary of genetic mutations in epigenetic genes and a review of CMP inhibitors suitable for preclinical studies or currently in clinical trials. Additionally, we highlight the CMPs for which potent inhibitors have not been developed and additional research focus should be dedicated. Copyright © 2017 Elsevier Ltd. All rights reserved.
Qureshi, Irfan A.
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. PMID:21671162
Chen, Diyu; Zuo, Yangjin; Zhang, Xinhua; Ye, Yuhua; Bao, Xiuqin; Huang, Haiyan; Tepakhan, Wanicha; Wang, Lijuan; Ju, Junyi; Chen, Guangfu; Zheng, Mincui; Liu, Dun; Huang, Shuodan; Zong, Lu; Li, Changgang; Chen, Yajun; Zheng, Chenguang; Shi, Lihong; Zhao, Quan; Wu, Qiang; Fucharoen, Supan; Zhao, Cunyou; Xu, Xiangmin
A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for β-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of β-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from β-thalassemia persons. The present study demonstrates that this common rSNP in the proximal (A)γ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of β-hemoglobinopathy. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
There is increasing evidence that abnormalities in epigenetic mechanisms of gene expression contribute to the development of multiple sclerosis (MS). Advances in epigenetics have given rise to a new class of drugs, epigenetic drugs. Although many classes of epigenetic drugs are being investigated, at present most attention is being paid to two classes of epigenetic drugs: drugs that inhibit DNA methyltransferase (DNMTi) and drugs that inhibit histone deacetylase (HDACi). This paper discusses ...
Full Text Available Recent studies have firmly established that the etiology of autism includes both genetic and environmental components. However, we are only just beginning to elucidate the environmental factors that might be involved in the development of autism, as well as the molecular mechanisms through which they function. Mounting epidemiological and biological evidence suggest that prenatal factors that induce a more activated immune state in the mother are involved in the development of autism. In parallel, molecular studies have highlighted the role of epigenetics in brain development as process susceptible to environmental influences and potentially causative of ASD. In this review, we will discuss converging evidence for a multidirectional interaction between immune system activation in the mother during pregnancy and epigenetic regulation in the brain of the fetus that may cooperate to produce an autistic phenotype. This interaction includes immune factor-induced changes in epigenetic signatures in the brain, dysregulation of epigenetic modifications specifically in genomic regions that encode immune functions, and aberrant epigenetic regulation of microglia. Overall, the interaction between immune system activation in the mother and the subsequent epigenetic dysregulation in the developing fetal brain may be a main consideration for the environmental factors that cause autism.
Bays, Harold; Scinta, Wendy
To examine the contribution of generational epigenetic dysregulation to the inception of obesity and its adiposopathic consequences. Sources for this review included searches of PubMed, Google Scholar, and international government/major association websites using terms including adiposity, adiposopathy, epigenetics, genetics, and obesity. Excessive energy storage in adipose tissue often results in fat cell and fat organ dysfunction, which may cause metabolic and fat mass disorders. The adverse clinical manifestations of obesity are not solely due to the amount of body fat (adiposity), but are also dependent on anatomical and functional perturbations (adiposopathy or 'sick fat'). This review describes extragenetic factors and genetic conditions that promote obesity. It also serves as an introduction to epigenetic dysregulation (i.e., abnormalities in gene expression that occur without alteration in the genetic code itself), which may contribute to obesity and adiposopathic metabolic health outcomes in offspring. Within the epigenetic paradigm, obesity is a transgenerational disease, with weight lost or gained by either parent potentially impacting generational risk for obesity and its complications. Epigenetics may be an important contributor to the emergence of obesity and its complications as global epidemics. Although transgenerational epigenetic influences present challenges, they may also present interventional opportunities, via justifying weight management for individuals before, during, and after pregnancy and for future generations.
Sierra, Marta I.; Fernández, Agustín F.; Fraga, Mario F.
The best-known phenomenon exemplifying epigenetic drift (the alteration of epigenetic patterns during aging) is the gradual decrease of global DNA methylation. Aging cells, different tissue types, as well as a variety of human diseases possess their own distinct DNA methylation profiles, although the functional impact of these is not always clear. DNA methylation appears to be a dynamic tool of transcriptional regulation, with an extra layer of complexity due to the recent discovery of the conversion of 5-methylcytosine into 5-hydroxymethylcytosine. This age-related DNA demethylation is associated with changes in histone modification patterns and, furthermore, we now know that ncRNAs have evolved in eukaryotes as epigenetic regulators of gene expression. In this review, we will discuss current knowledge on how all these epigenetic phenomena are implicated in human aging, and their links with external, internal and stochastic factors which can affect human age-related diseases onset. PMID:27019618
Campión, Javier; Milagro, Fermin; Martínez, J Alfredo
The etiology of obesity is multifactorial, involving complex interactions among the genetic makeup, neuroendocrine status, fetal programming, and different unhealthy environmental factors, such as sedentarism or inadequate dietary habits. Among the different mechanisms causing obesity, epigenetics, defined as the study of heritable changes in gene expression that occur without a change in the DNA sequence, has emerged as a very important determinant. Experimental evidence concerning dietary factors influencing obesity development through epigenetic mechanisms has been described. Thus, identification of those individuals who present with changes in DNA methylation profiles, certain histone modifications, or other epigenetically related processes could help to predict their susceptibility to gain or lose weight. Indeed, research concerning epigenetic mechanisms affecting weight homeostasis may play a role in the prevention of excessive fat deposition, the prediction of the most appropriate weight reduction plan, and the implementation of newer therapeutic approaches.
DNA and histone methylation have been implicated in epigenetic gene regulation. Recent studies in Neurospora and now Arabidopsis indicate that histone methylation can direct DNA methylation, suggesting that these two methylation systems have been functionally linked during evolution.
Jorgensen, Richard A
The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920s and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene - the molecular biological view and the epigenetic view - are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider.
Durham, Andrew L; Wiegman, Coen; Adcock, Ian M
Asthma is caused by both heritable and environmental factors. It has become clear that genetic studies do not adequately explain the heritability and susceptibility to asthma. The study of epigenetics, heritable non-coding changes to DNA may help to explain the heritable component of asthma. Additionally, epigenetic modifications can be influenced by the environment, including pollution and cigarette smoking, which are known asthma risk factors. These environmental trigger-induced epigenetic changes may be involved in skewing the immune system towards a Th2 phenotype following in utero exposure and thereby enhancing the risk of asthma. Alternatively, they may directly or indirectly modulate the immune and inflammatory processes in asthmatics via effects on treatment responsiveness. The study of epigenetics may therefore play an important role in our understanding and possible treatment of asthma and other allergic diseases. This article is part of a Special Issue entitled: Biochemistry of Asthma.
Richard A Jorgensen
Full Text Available The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920's and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene - the molecular biological view and the epigenetic view - are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider.
Wenyi Xu; Fengzhong Wang; Zhongsheng Yu; Fengjiao Xin
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 proce...
Vatan, Sevginar; Lester, David; Gunn, John F
A sample of 87 Turkish undergraduate students was administered scales to measure hopelessness, problem-solving skills, emotion dysregulation, and psychiatric symptoms. All of the scores from these scales were strongly associated. In a multiple regression, hopelessness scores were predicted by poor problem-solving skills and emotion dysregulation.
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
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.
Barrow, Timothy M; Michels, Karin B
Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.
Drummond, Elaine M; Gibney, Eileen R
Research suggests that 65% of variation in obesity is genetic. However, much of the known genetic associations have little known function and their effect size small, thus the gene-environment interaction, including epigenetic influences on gene expression, is suggested to be an important factor in the susceptibilty to obesity. This review will explore the potential of epigenetic markers to influence expression of genes associated with obesity. Epigenetic changes in utero are known to have direct implications on the phenotype of the offspring. More recently work has focused on how such epigenetic changes continue to regulate risk of obesity from infancy through to adulthood. Work has shown that, for example, hypomethylation of the MC4 gene causes an increase in expression, and has a direct impact on appetite and intake, and thus influences risk of obesity. Similar influences are also seen in other aspects of obesity including inflammation and adiposity. Maternal diet during foetal development has many epigenetic implications, which affect the offspring's risk factors for obesity during childhood and adulthood, and even in subsequent generations. Genes associated with risk of obesity, are susceptible to epigenetic mutations, which have subsequent effects on disease mechanisms, such as appetite and impaired glucose and insulin tolerance.
Nutritional epigenetics has emerged as a novel mechanism underlying gene–diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modu...
Yan, Jie; Yang, Huixia
Gestational diabetes mellitus (GDM) is a common medical complication in pregnancy. Offspring exposed to maternal hyperglycemia have a higher birth weight and are prone to develop metabolic disease in adult life. The intrauterine environmental or nutritional status seems to be involved in the fetal programing. The concept of "Developmental Origins of Health and Disease" (DOHaD) has been widely accepted and it brings new insights into the molecular pathogenesis of human diseases. The underlying mechanism is still under discussion and epigenetic mechanisms may provide an explanation for the phenomenon. The aim of this review is to illustrate the role of epigenetic modifications in the development of insulin resistance in metabolic diseases induced by adverse intrauterine exposures. Changes in epigenetic mechanism may be an early event in pathogenesis and progression of the metabolic disease in humans. Studies on epigenetic modifications contribute to our understanding of long-term effects of in utero exposure and shed light on the disease prevention and treatment by modulating epigenetic changes.
McConoughey, Stephen J; Basso, Manuela; Niatsetskaya, Zoya V; Sleiman, Sama F; Smirnova, Natalia A; Langley, Brett C; Mahishi, Lata; Cooper, Arthur J L; Antonyak, Marc A; Cerione, Rick A; Li, Bo; Starkov, Anatoly; Chaturvedi, Rajnish Kumar; Beal, M Flint; Coppola, Giovanni; Geschwind, Daniel H; Ryu, Hoon; Xia, Li; Iismaa, Siiri E; Pallos, Judit; Pasternack, Ralf; Hils, Martin; Fan, Jing; Raymond, Lynn A; Marsh, J Lawrence; Thompson, Leslie M; Ratan, Rajiv R
Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.
Elhamamsy, Amr Rafat
DNA methylation is a major epigenetic marking mechanism regulating various biological functions in mammals and plant. The crucial role of DNA methylation has been observed in cellular differentiation, embryogenesis, genomic imprinting and X-chromosome inactivation. Furthermore, DNA methylation takes part in disease susceptibility, responses to environmental stimuli and the biodiversity of natural populations. In plant, different types of environmental stress have demonstrated the ability to alter the archetype of DNA methylation through the genome, change gene expression and confer a mechanism of adaptation. DNA methylation dynamics are regulated by three processes de novo DNA methylation, methylation maintenance and DNA demethylation. These processes have their similarities and differences between mammals and plants. Furthermore, the dysregulation of DNA methylation dynamics represents one of the primary molecular mechanisms of developing diseases in mammals. This review discusses the regulation and dysregulation of DNA methylation in plants and mammals. Copyright © 2016 John Wiley & Sons, Ltd.
Froyen, Guy; Bauters, Marijke; Voet, Thierry; Marynen, Peter
The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.
Álvarez-Errico, Damiana; Vento-Tormo, Roser; Ballestar, Esteban
The concept of autoinflammation has evolved over the past 20 years, beginning with the discovery that mutations in the Mediterranean Fever (MEFV) gene were causative of Familial Mediterranean Fever. Currently, autoinflammatory diseases comprise a wide range of disorders with the common features of recurrent fever attacks, prevalence of hyperreactive innate immune cells, and signs of inflammation that can be systemic or organ specific in the absence of pathogenic infection of autoimmunity. Innate immune cells from the myeloid compartment are the main effectors of uncontrolled inflammation that is caused in great extent by the overproduction of inflammatory cytokines such as IL-1β and IL-18. Defects in several signaling pathways that control innate immune defense, particularly the hyperreactivity of one or more inflammasomes, are at the core of pathologic autoinflammatory phenotypes. Although many of the autoinflammatory syndromes are known to be monogenic, some of them are genetically complex and are impacted by environmental factors. Recently, epigenetic dysregulation has surfaced as an additional contributor to pathogenesis. In the present review, we discuss data that are currently available to describe the contribution of epigenetic mechanisms in autoinflammatory diseases.
Lopomo, A; Burgio, E; Migliore, L
Obesity is a metabolic disease, which is becoming an epidemic health problem: it has been recently defined in terms of Global Pandemic. Over the years, the approaches through family, twins and adoption studies led to the identification of some causal genes in monogenic forms of obesity but the origins of the pandemic of obesity cannot be considered essentially due to genetic factors, because human genome is not likely to change in just a few years. Epigenetic studies have offered in recent years valuable tools for the understanding of the worldwide spread of the pandemic of obesity. The involvement of epigenetic modifications-DNA methylation, histone tails, and miRNAs modifications-in the development of obesity is more and more evident. In the epigenetic literature, there are evidences that the entire embryo-fetal and perinatal period of development plays a key role in the programming of all human organs and tissues. Therefore, the molecular mechanisms involved in the epigenetic programming require a new and general pathogenic paradigm, the Developmental Origins of Health and Disease theory, to explain the current epidemiological transition, that is, the worldwide increase of chronic, degenerative, and inflammatory diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. Obesity and its related complications are more and more associated with environmental pollutants (obesogens), gut microbiota modifications and unbalanced food intake, which can induce, through epigenetic mechanisms, weight gain, and altered metabolic consequences.
XU Xue-feng; DU Li-zhong
Objective To review the role of epigenetic regulation in neonatal diseases and better understand Barker's "fetal origins of adult disease hypothesis".Data sources The data cited in this review were mainly obtained from the articles published in Medline/PubMed between January 1953 and December 2009.Study selection Articles associated with epigenetics and neonatal diseases were selected.Results There is a wealth of epidemiological evidence that lower birth weight is strongly correlated with an increased risk of adult diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular disease. This phenomenon of fetal origins of adult disease is strongly associated with fetal insults to epigenetic modifications of genes. A potential role of epigenetic modifications in congenital disorders, transient neonatal diabetes mellitus (TNDM), intrauterine growth retardation (IUGR), and persistent pulmonary hypertension of the newborn (PPHN) have been studied.Conclusions Acknowledgment of the role of these epigenetic modifications in neonatal diseases would be conducive to better understanding the pathogenesis of these diseases, and provide new insight for improved treatment and prevention of later adult diseases.
Cortini, Ruggero; Barbi, Maria; Caré, Bertrand R.; Lavelle, Christophe; Lesne, Annick; Mozziconacci, Julien; Victor, Jean-Marc
In higher organisms, all cells share the same genome, but every cell expresses only a limited and specific set of genes that defines the cell type. During cell division, not only the genome, but also the cell type is inherited by the daughter cells. This intriguing phenomenon is achieved by a variety of processes that have been collectively termed epigenetics: the stable and inheritable changes in gene expression patterns. This article reviews the extremely rich and exquisitely multiscale physical mechanisms that govern the biological processes behind the initiation, spreading, and inheritance of epigenetic states. These include not only the changes in the molecular properties associated with the chemical modifications of DNA and histone proteins, such as methylation and acetylation, but also less conventional changes, typically in the physics that governs the three-dimensional organization of the genome in cell nuclei. Strikingly, to achieve stability and heritability of epigenetic states, cells take advantage of many different physical principles, such as the universal behavior of polymers and copolymers, the general features of dynamical systems, and the electrostatic and mechanical properties related to chemical modifications of DNA and histones. By putting the complex biological literature in this new light, the emerging picture is that a limited set of general physical rules play a key role in initiating, shaping, and transmitting this crucial "epigenetic landscape." This new perspective not only allows one to rationalize the normal cellular functions, but also helps to understand the emergence of pathological states, in which the epigenetic landscape becomes dysfunctional.
Roopra, Avtar; Dingledine, Raymond; Hsieh, Jenny
Seizures can give rise to enduring changes that reflect alterations in gene-expression patterns, intracellular and intercellular signaling, and ultimately network alterations that are a hallmark of epilepsy. A growing body of literature suggests that long-term changes in gene transcription associated with epilepsy are mediated via modulation of chromatin structure. One transcription factor in particular, repressor element 1-silencing transcription factor (REST), has received a lot of attention due to the possibility that it may control fundamental transcription patterns that drive circuit excitability, seizures, and epilepsy. REST represses a suite of genes in the nervous system by utilizing nuclear protein complexes that were originally identified as mediators of epigenetic inheritance. Epigenetics has traditionally referred to mechanisms that allow a heritable change in gene expression in the absence of DNA mutation. However a more contemporaneous definition acknowledges that many of the mechanisms used to perpetuate epigenetic traits in dividing cells are utilized by neurons to control activity-dependent gene expression. This review surveys what is currently understood about the role of epigenetic mechanisms in epilepsy. We discuss how REST controls gene expression to affect circuit excitability and neurogenesis in epilepsy. We also discuss how the repressor methyl-CpG-binding protein 2 (MeCP2) and activator cyclic AMP response element binding protein (CREB) regulate neuronal activity and are themselves controlled by activity. Finally we highlight possible future directions in the field of epigenetics and epilepsy.
Full Text Available Schizophrenia is a complex psychiatric disorder characterized by the presence of positive, negative and cognitive symptoms that lacks a unifying neuropathology. In the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including genetic and epigenetic studies. In relation to the latter, basic research suggests that normal cognition is regulated by epigenetic mechanisms and its dysfunction occurs upon epigenetic misregulation, providing new insights into missing heritability of complex psychiatric diseases, referring to the discrepancy between epidemiological heritability and the proportion of phenotypic variation explained by DNA sequence difference. In schizophrenia the absence of consistently replicated genetic effects together with evidence for lasting changes in gene expression after environmental exposures suggest a role of epigenetic mechanisms. In this review we will focus on epigenetic modifications as a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychotic conditions throughout life.
Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.
Patel, Trupti N; Roy, Soumyadipta; Ravi, Revathi
Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease. PMID:28144288
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
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 miRNA expression. It has been identified that several lifestyle factors such as diet, obesity, physical activity, tobacco smoking, alcohol consumption, environmental pollutants, psychological stress and working on night shifts might modify epigenetic patterns. Most of the 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. This article reviews current evidence indicating that lifestyle factors might affect human health via epigenetic mechanisms.
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
Bartlett, Andrew A; Singh, Rumani; Hunter, Richard G
Anxiety disorders are highly prevalent psychiatric disorders often comorbid with depression and substance abuse. Twin studies have shown that anxiety disorders are moderately heritable. Yet, genome-wide association studies (GWASs) have failed to identify gene(s) significantly associated with diagnosis suggesting a strong role for environmental factors and the epigenome. A number of anxiety disorder subtypes are considered "stress related." A large focus of research has been on the epigenetic and anxiety-like behavioral consequences of stress. Animal models of anxiety-related disorders have provided strong evidence for the role of stress on the epigenetic control of the hypothalamic-pituitary-adrenal (HPA) axis and of stress-responsive brain regions. Neuroepigenetics may continue to explain individual variation in susceptibility to environmental perturbations and consequently anxious behavior. Behavioral and pharmacological interventions aimed at targeting epigenetic marks associated with anxiety may prove fruitful in developing treatments.
Cortini, Ruggero; Caré, Bertrand R; Lavelle, Christophe; Lesne, Annick; Mozziconacci, Julien; Victor, Jean-Marc
In higher organisms, all cells share the same genome, but every cell expresses only a limited and specific set of genes that defines the cell type. During cell division, not only the genome, but also the cell type is inherited by the daughter cells. This intriguing phenomenon is achieved by a variety of processes that have been collectively termed epigenetics: the stable and inheritable changes in gene expression patterns. This article reviews the extremely rich and exquisitely multi-scale physical mechanisms that govern the biological processes behind the initiation, spreading and inheritance of epigenetic states. These include not only the change in the molecular properties associated with the chemical modifications of DNA and histone proteins - such as methylation and acetylation - but also less conventional ones, such as the physics that governs the three-dimensional organization of the genome in cell nuclei. Strikingly, to achieve stability and heritability of epigenetic states, cells take advantage of m...
Ingela Djupedal; Karl Ekwall
The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, important for maintaining genome integrity but also for silencing of genes within. Small RNA, together with factors typically associated with RNA interference (RNAi) targets homologous DNA sequences and recruits factors that modify the chromatin, com-monly resulting in formation of heterochromatin and silencing of target genes. The scope of this review is to provide an overview of the roles of small RNA and the RNAi components, Dicer, Argonaute and RNA dependent polymeras-es in epigenetic inheritance via heterochromatin formation, exemplified with pathways from unicellular eukaryotes, plants and animals.
Yang, Ya-ran; Wang, Peng-xiang; Fang, Xiang-dong; Yan, Jiang-wei
Epigenetics is the study of heritable changes in gene expression other than changes in the underlying DNA sequence. Such changes include DNA methylation, histone modification, chromatin remodeling, genomic imprinting, X chromosome inactivation and non-coding RNA regulation. Recent progresses on epigenetics open new possibilities in tackling these challenging problems in forensic science, including identification of fetal paternity testing in embryonic period, determination of the necessary allele in paternity testing, discrimination of identical twins, origination analysis of micro tissue, verification of forged DNA. This review focuses on epigenetics concept and its latest application in the field of paternity testing, age estimation, discrimination between the twins, identification of tissue of origin, and estimation of postmortem interval.
Remely, M; Lovrecic, L; de la Garza, A L; Migliore, L; Peterlin, B; Milagro, F I; Martinez, A J; Haslberger, A G
Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction. PMID:25046997
Tesi, Bianca; Schlums, Heinrich; Cichocki, Frank; Bryceson, Yenan T
Natural killer (NK) cells were previously considered to represent short-lived, innate lymphocytes. However, mouse models have revealed expansion and persistence of differentiated NK cell subsets in response to cytomegalovirus (CMV) infection, paralleling antigen-specific T cell differentiation. Congruently, analyses of humans have uncovered CMV-associated NK cell subsets characterized by epigenetic diversification processes that lead to altered target cell specificities and functional capacities. Here, focusing on responses to viruses, we review similarities and differences between mouse and human adaptive NK cells, identifying molecular analogies that may be key to transcriptional reprogramming and functional alterations. We discuss possible molecular mechanisms underlying epigenetic diversification and hypothesize that processes driving epigenetic diversification may represent a more widespread mechanism for fine-tuning and optimization of cellular immunity.
Henikoff, Steven; Smith, M. Mitchell
Histones package and compact DNA by assembling into nucleosome core particles. Most histones are synthesized at S phase for rapid deposition behind replication forks. In addition, the replacement of histones deposited during S phase by variants that can be deposited independently of replication provide the most fundamental level of chromatin differentiation. Alternative mechanisms for depositing different variants can potentially establish and maintain epigenetic states. Variants have also evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, and other processes. Investigations into the evolution, structure, and metabolism of histone variants provide a foundation for understanding the participation of chromatin in important cellular processes and in epigenetic memory. PMID:25561719
Kassis, Haifa; Shehadah, Amjad; Chopp, Michael; Zhang, Zheng Gang
Abstract: While the death rate from stroke has continually decreased due to interventions in the hyperacute stage of the disease, long-term disability and institutionalization have become common sequelae in the aftermath of stroke. Therefore, identification of new molecular pathways that could be targeted to improve neurological recovery among survivors of stroke is crucial. Epigenetic mechanisms such as post-translational modifications of histone proteins and microRNAs have recently emerged as key regulators of the enhanced plasticity observed during repair processes after stroke. In this review, we highlight the recent advancements in the evolving field of epigenetics in stroke recovery. PMID:28264471
Dynamic aspects of melatonin's actions merit increasing future attention. This concerns particularly entirely different effects in senescent, weakened oscillators and in dysregulated oscillators of cancer cells that may be epigenetically blocked. This is especially obvious in the case of sirtuin 1, which is upregulated by melatonin in aged tissues, but strongly downregulated in several cancer cells. These findings are not at all controversial, but are explained on the basis of divergent changes in weakened and dysregulated oscillators. Similar findings can be expected to occur in other accessory oscillator components that are modulated by melatonin, among them several transcription factors and metabolic sensors. Another cause of opposite effects concerns differences between nocturnally active laboratory rodents and the diurnally active human. This should be more thoroughly considered in the field of metabolic syndrome and related pathologies, especially with regard to type 2 diabetes and other aspects of insulin resistance. Melatonin was reported to impair glucose tolerance in humans, especially in carriers of the risk allele of the MT2 receptor gene, MTNR1B, that contains the SNP rs10830963. These findings contrast with numerous reports on improvements of glucose tolerance in preclinical studies. However, the relationship between melatonin and insulin may be more complex, as indicated by loss-of-function mutants of the MT2 receptor that are also prodiabetic, by the age-dependent time course of risk allele overexpression, by progressive reduction in circadian amplitudes and melatonin secretion, which are aggravated in diabetes. By supporting high-amplitude rhythms, melatonin may be beneficial in preventing or delaying diabetes.
Crescio, Claudia; Orecchioni, Marco; Ménard-Moyon, Cécilia; Sgarrella, Francesco; Pippia, Proto; Manetti, Roberto; Bianco, Alberto; Delogu, Lucia Gemma
Spaceflights lead to dysregulation of the immune cell functionality affecting the expression of activation markers and cytokine production. Short oxidized multi-walled carbon nanotubes functionalized by 1,3-dipolar cycloaddition have been reported to activate immune cells. In this Communication we have performed surface marker assays and multiplex ELISA on primary monocytes and T cells under microgravity. We have discovered that carbon nanotubes, through their immunostimulatory properties, are able to fight spaceflight immune system dysregulations.
Smulders, M.J.M.; Klerk, de G.J.M.
Plants produced vegetatively in tissue culture may differ from the plants from which they have been derived. Two major classes of off-types occur: genetic ones and epigenetic ones. This review is about epigenetic aberrations. We discuss recent studies that have uncovered epigenetic modifications at
Pivarunas, Bernadette; Conner, Bradley T
Food addiction is the clinical occurrence in which individuals develop physical and psychological dependencies on high fat, high sugar, and highly palatable foods. Past research has demonstrated a number of similarities between food addiction and drug use disorders including the activation of specific brain regions and neurotransmitters, disrupted neuronal circuitry, and behavioral indicators of addiction such as continued use despite negative consequences. The present study examined the role of impulsivity and emotion dysregulation in food addiction as both play salient roles in drug use disorders. Poisson regression analyses using data from 878 undergraduate students revealed negative urgency, the tendency to act impulsively when under distress, and emotion dysregulation positively predicted symptom count on the Yale Food Addiction Scale (Gearhardt, Corbin, & Brownell, 2009) whereas a lack of premeditation negatively predicted symptom count (all psaddiction, elucidate causal mechanisms, and support an explanatory model of food addiction.
Ahuja, Nita; Sharma, Anup R; Baylin, Stephen B
The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.
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.
Pickersgill, Martyn; Niewöhner, Jörg; Müller, Ruth; Martin, Paul; Cunningham-Burley, Sarah
Epigenetics is the study of changes in gene expression caused by mechanisms other than changes in the DNA itself. The field is rapidly growing and being widely promoted, attracting attention in diverse arenas. These include those of the social sciences, where some researchers have been encouraged by the resonance between imaginaries of development within epigenetics and social theory. Yet, sustained attention from science and technology studies (STS) scholars to epigenetics and the praxis it propels has been lacking. In this article, we reflexively consider some of the ways in which epigenetics is being constructed as an area of biomedical novelty and discuss the content and logics underlying the ambivalent promises being made by scientists working in this area. We then reflect on the scope, limits and future of engagements between epigenetics and the social sciences. Our discussion is situated within wider literatures on biomedicine and society, the politics of "interventionist STS," and on the problems of "caseness" within empirical social science.
Sarkar, Sibaji; Horn, Garrick; Moulton, Kimberly; Oza, Anuja; Byler, Shannon; Kokolus, Shannon; Longacre, McKenna
Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell-cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.
Dubey, Akanksha; Jeon, Junhyun
Evidently, epigenetics is at forefront in explaining the mechanisms underlying the success of human pathogens and in the identification of pathogen-induced modifications within host plants. However, there is a lack of studies highlighting the role of epigenetics in the modulation of the growth and pathogenicity of fungal plant pathogens. In this review, we attempt to highlight and discuss the role of epigenetics in the regulation of the growth and pathogenicity of fungal phytopathogens using Magnaporthe oryzae, a devastating fungal plant pathogen, as a model system. With the perspective of wide application in the understanding of the development, pathogenesis and control of other fungal pathogens, we attempt to provide a synthesized view of the epigenetic studies conducted on M. oryzae to date. First, we discuss the mechanisms of epigenetic modifications in M. oryzae and their impact on fungal development and pathogenicity. Second, we highlight the unexplored epigenetic mechanisms and areas of research that should be considered in the near future to construct a holistic view of epigenetic functioning in M. oryzae and other fungal plant pathogens. Importantly, the development of a complete understanding of the modulation of epigenetic regulation in fungal pathogens can help in the identification of target points to combat fungal pathogenesis. © 2016 BSPP AND JOHN WILEY & SONS LTD.
Guanghua, Xiao; Xinlei, Wang; Quincey, LaPlant; Nestler, Eric J; Xie, Yang
Identification of genome-wide epigenetic changes, the stable changes in gene function without a change in DNA sequence, under various conditions plays an important role in biomedical research. High-throughput epigenetic experiments are useful tools to measure genome-wide epigenetic changes, but the measured intensity levels from these high-resolution genome-wide epigenetic profiling data are often spatially correlated with high noise levels. In addition, it is challenging to detect genome-wide epigenetic changes across multiple conditions, so efficient statistical methodology development is needed for this purpose. In this study, we consider ANOVA models with spatially varying coefficients, combined with a hierarchical Bayesian approach, to explicitly model spatial correlation caused by location-dependent biological effects (i.e., epigenetic changes) and borrow strength among neighboring probes to compare epigenetic changes across multiple conditions. Through simulation studies and applications in drug addiction and depression datasets, we find that our approach compares favorably with competing methods; it is more efficient in estimation and more effective in detecting epigenetic changes. In addition, it can provide biologically meaningful results.
Full Text Available Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell–cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.
Lao, Victoria Valinluck; Grady, William M.
Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203
It is not really helpful to consider modern environmental epigenetics as neo-Lamarckian; and there is no evidence that Lamarck considered the idea original to himself. We must all keep learning about inheritance, but attributing modern ideas to early researchers is not helpful, and can be misleading. PMID:26026157
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.
Myrtue Nielsen, Helene; Lykkegaard Andersen, Christen; Westman, Maj
, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation...
There is increasing evidence that abnormalities in epigenetic mechanisms of gene expression contribute to the development of multiple sclerosis (MS). Advances in epigenetics have given rise to a new class of drugs, epigenetic drugs. Although many classes of epigenetic drugs are being investigated, at present most attention is being paid to two classes of epigenetic drugs: drugs that inhibit DNA methyltransferase (DNMTi) and drugs that inhibit histone deacetylase (HDACi). This paper discusses the potential use of epigenetic drugs in the treatment of MS, focusing on DNMTi and HDACi. Preclinical drug trials of DNMTi and HDACi for the treatment of MS are showing promising results. Epigenetic drugs could improve the clinical management of patients with MS.
Cicatelli, Angela; Baldantoni, Daniela; Iovieno, Paola; Carotenuto, Maurizio; Alfani, Anna; De Feis, Italia; Castiglione, Stefano
The use of compost for soil amendment is a promising agricultural practice environmentally and economically viable. In the framework of a wide research project designed to evaluate the effects of soil amendment with municipal solid waste compost in comparison with traditional mineral fertilization practices, 54 different cultivars (Cvs) of potatoes were AFLP (amplified fragment length polymorphism) molecularly fingerprinted. The seven most genetically biodiverse potato Cvs were used to establish an experimental field in southern Italy. The field area was divided into two portions fertilized with compost (20 Mg ha(-1)) or with ammonium sulphate (200 kg ha(-1)). No significant differences in productivity, organoleptic characteristics and element concentrations were observed between the potato tubers obtained with both kinds of soil fertilization, while the tubers grown on compost amended soil showed, on average, higher K concentrations with respect to those grown on mineral fertilised soil. cDNA-AFLP (complementary DNA-AFLP) and MSAP (methylation sensitive amplified polymorphism) analyses were carried out on both leaves and tubers of one selected Cv to estimate if any transcriptome alterations or epigenetic modifications were induced by the two kinds of fertilization, however no variations were detected. Chemical and biological soil qualities (i.e., microbial respiration, FDA hydrolysis, alkaline and acid phosphatase) were assessed on soil samples at the start of the experiment and at the end of potato crop cycle. No significant differences in soil pH and limited ones, in the available fraction of some trace elements, were observed; while conductivity was much higher for the compost amended portion of the experimental field. Microbial respiration, FDA hydrolysis and acid phosphatase activities were significantly increased by compost amendment, in comparison with mineral fertilization. Finally, a sensory panel of potato Cvs detected no significant differences among
Foust, C M; Preite, V; Schrey, A W; Alvarez, M; Robertson, M H; Verhoeven, K J F; Richards, C L
While traits and trait plasticity are partly genetically based, investigating epigenetic mechanisms may provide more nuanced understanding of the mechanisms underlying response to environment. Using AFLP and methylation-sensitive AFLP, we tested the hypothesis that differentiation to habitats along natural salt marsh environmental gradients occurs at epigenetic, but not genetic loci in two salt marsh perennials. We detected significant genetic and epigenetic structure among populations and among subpopulations, but we found multilocus patterns of differentiation to habitat type only in epigenetic variation for both species. In addition, more epigenetic than genetic loci were correlated with habitat in both species. When we analysed genetic and epigenetic variation simultaneously with partial Mantel, we found no correlation between genetic variation and habitat and a significant correlation between epigenetic variation and habitat in Spartina alterniflora. In Borrichia frutescens, we found significant correlations between epigenetic and/or genetic variation and habitat in four of five populations when populations were analysed individually, but there was no significant correlation between genetic or epigenetic variation and habitat when analysed jointly across the five populations. These analyses suggest that epigenetic mechanisms are involved in the response to salt marsh habitats, but also that the relationships among genetic and epigenetic variation and habitat vary by species. Site-specific conditions may also cloud our ability to detect response in replicate populations with similar environmental gradients. Future studies analysing sequence data and the correlation between genetic variation and DNA methylation will be powerful to identify the contributions of genetic and epigenetic response to environmental gradients.
Lomniczi, Alejandro; Loche, Alberto; Castellano, Juan Manuel; Ronnekleiv, Oline K.; Bosch, Martha; Kaidar, Gabi; Knoll, J. Gabriel; Wright, Hollis; Pfeifer, Gerd. P.; Ojeda, Sergio R.
The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as major contributors to this mechanism, and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreases and methylation of their promoters increases preceding puberty. Inhibiting DNA methylation blocks both events and results in pubertal failure. The pubertal increase in Kiss1 is accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupts pulsatile GnRH release, delays puberty, and compromises fecundity. Our results identify epigenetic silencing as a novel mechanism underlying the neuroendocrine control of female puberty. PMID:23354331
Full Text Available Cardiovascular disease (CVD remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs and deacetylases (HDACs are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.
Roy, Ram Vinod; Son, Young-Ok; Pratheeshkumar, Poyil; Wang, Lei; Hitron, John Andrew; Divya, Sasidharan Padmaja; D, Rakesh; Kim, Donghern; Yin, Yuanqin; Zhang, Zhuo; Shi, Xianglin
DNA methylation and histone modification promote opening and closure of chromatin structure, which affects gene expression without altering the DNA sequence. Epigenetic markers regulate the dynamic nature of chromatin structure at different levels: DNA, histone, noncoding RNAs, as well as the higher-order chromatin structure. Accumulating evidence strongly suggests that arsenic-induced carcinogenesis involves frequent changes in the epigenetic marker. However, progress in identifying arsenic-induced epigenetic changes has already been made using genome-wide approaches; the biological significance of these epigenetic changes remains unknown. Moreover, arsenic-induced changes in the chromatin state alter gene expression through the epigenetic mechanism. The current review provides a summary of recent literature regarding epigenetic changes caused by arsenic in carcinogenesis. We highlight the transgenerational studies needed to explicate the biological significance and toxicity of arsenic over a broad spectrum.
Vandegehuchte, Michiel B; Janssen, Colin R
Epigenetics can play a role in interactions between chemicals and exposed species, between species and abiotic ecosystem components or between species of the same or another population in a community. Technological progress and advanced insights into epigenetic processes have led to the description of epigenetic features (mainly DNA methylation) in many ecologically relevant species: algae, plants, several invertebrates and fish. Epigenetic changes in plants, insects and cladocerans have been reported to be induced by various environmental stress factors including nutrition or water deficiency, grazing, light or temperature alterations, social environment, and dissolved organic matter concentrations. As regards chemicals, studies in rats and mice exposed to specific pesticides, hydrocarbons, dioxins, and endocrine disrupting chemicals demonstrated the induction of epigenetic changes, suggesting the need for further research with these substances in an ecotoxicological context. In fish and plants, exposure to polyaromatic hydrocarbons, metals, and soluble fractions of solid waste affected the epigenetic status. A novel concept in ecotoxicological epigenetics is the induction of transgenerational stress resistance upon chemical exposure, as demonstrated in rice exposed to metals. Evaluating epigenetics in ecotoxicological field studies is a second relatively new approach. A cryptic lineage of earthworms had developed arsenic tolerance in the field, concurrent with specific DNA methylation patterns. Flatfish caught in the framework of environmental monitoring had developed tumours, exhibiting specific DNA methylation patterns. Two main potential implications of epigenetics in an ecotoxicological context are (1) the possibility of transgenerationally inherited, chemical stress-induced epigenetic changes with associated phenotypes and (2) epigenetically induced adaptation to stress upon long-term chemical exposure. Key knowledge gaps are concerned with the causality of
Keverne, Eric B
Fundamental aspects of mammalian brain evolution occurred in the context of viviparity and placentation brought about by the epigenetic regulation of imprinted genes. Since the fetal placenta hormonally primes the maternal brain, two genomes in one individual are transgenerationally co-adapted to ensure maternal care and nurturing. Advanced aspects of neocortical brain evolution has shown very few genetic changes between monkeys and humans. Although these lineages diverged at approximately the same time as the rat and mouse (20 million years ago), synonymous sequence divergence between the rat and mouse is double that when comparing monkey with human sequences. Paradoxically, encephalization of rat and mouse are remarkably similar, while comparison of the human and monkey shows the human cortex to be three times the size of the monkey. This suggests an element of genetic stability between the brains of monkey and man with a greater emphasis on epigenetics providing adaptable variability.
Qureshi, Irfan A; Mehler, Mark F
Epilepsy refers to a heterogeneous group of disorders that are associated with a wide range of pathogenic mechanisms, seizure manifestations, comorbidity profiles, and therapeutic responses. These characteristics are all influenced quite significantly by sex. As with other conditions exhibiting such patterns, sex differences in epilepsy are thought to arise-at the most fundamental level-from the "organizational" and "activational" effects of sex hormones as well as from the direct actions of the sex chromosomes. However, our understanding of the specific molecular, cellular, and network level processes responsible for mediating sex differences in epilepsy remains limited. Because increasing evidence suggests that epigenetic mechanisms are involved both in epilepsy and in brain sexual dimorphism, we make the case here that analyzing epigenetic regulation will provide novel insights into the basis for sex differences in epilepsy.
Copray, Sjef; Huynh, Jimmy Long; Sher, Falak; Casaccia-Bonnefil, Patrizia; Boddeke, Erik
The process of oligodendrocyte differentiation is regulated by a dynamic interaction between a genetic and an epigenetic program. Recent studies, addressing nucleosomal histone modifications have considerably increased our knowledge regarding epigenetic regulation of gene expression during oligodendrocyte development and aging. These results have generated new hypotheses regarding the mechanisms underlying the decreased efficiency of endogenous remyelination in response to demyelinating injuries with increasing age. In this review, we present an overview of the epigenetic mechanisms regulating gene expression at specific stages of oligodendrocyte differentiation and maturation as well as the changes that occur with aging.
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.
Full Text Available to neighbouring euchromatic genes, known as position effect variegation and can be transmitted through mitosis, forming the basis of epigenetic inheritance from one cell generation to another; creating cellular memory (Brzeski and Jerzmanowski, 2004... life form, supports meiosis that produces haploid male and female spores and initiates the gametophytic generation. Gametogenesis and subsequent fertilisation take place when gametophytic and sporophytic structures interact. The product...
Iguchi, Eriko; Safgren, Stephanie L; Marks, David L; Olson, Rachel L; Fernandez-Zapico, Martin E
Pancreatic cancer is the third leading cause of cancer mortality in the U.S. with close to 40,000 deaths per year. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90 percent of all pancreatic cancer cases and is the most lethal form of the disease. Current therapies for PDAC are ineffective and most patients cannot be treated by surgical resection. Most research efforts have primarily focused on how genetic alterations cause, alter progression, contribute to diagnosis, and influence PDAC management. Over the past two decades, a model has been advanced of PDAC initiation and progression as a multi-step process driven by the acquisition of mutations leading to loss of tumor suppressors and activation of oncogenes. The recognition of the essential roles of these genetic alterations in the development of PDAC has revolutionized our knowledge of this disease. However, none of these findings have turned into effective treatment for this dismal malignancy. In recent years, studies in the areas of chromatin modifications, and non-coding RNAs have uncovered mechanisms for regulating gene expression which occur independently of genetic alterations. Chromatin-based mechanisms are interwoven with microRNA-driven regulation of protein translation to create an integrated epigenetic language, which is grossly dysregulated in PDAC. Thus in PDAC, key tumor suppressors that are well established to play a role in PDAC may be repressed, and oncogenes can be upregulated secondary to epigenetic alterations. Unlike mutations, epigenetic changes are potentially reversible. Given this feature of epigenetic mechanisms, it is conceivable that targeting epigenetic-based events promoting and maintaining PDAC could serve as foundation for the development of new therapeutic and diagnostic approaches for this disease.
Meda, Francesca; Folci, Marco; Baccarelli, Andrea; Selmi, Carlo
The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years, several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases. PMID:21278766
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.
Maric, Nadja P; Svrakic, Dragan M
Schizophrenia (SZ) is a highly heritable disorder, with about 80% of the variance attributable to genetic factors. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SZ. On the other hand, rare and large copy number variants (CNVs) with high but incomplete penetrance, variable in different individual, could explain about additional 30% of SZ cases. Although these rare CNVs frequently develop de novo, it is not clear whether they affect risk independently or via interaction with a polygenic liability in the background. Finally, the role of environmental risk factors has been well established in SZ. Environmental factors are rarely sufficient to cause SZ independently, but act in parallel or in synergy with the underlying genetic liability. Epigenetic misregulation of the genome and direct CNS injury are probably the main mechanism to mediate prenatal environmental effects (e.g., viruses, ethanol, or nutritional deficiency) whereas postnatal risk factors (e.g., stress, urbanicity, cannabis use) may also affect risk via use-based potentiation of vulnerable CNS pathways implicated in SZ. In this review, we outline a general theoretical background of epigenetic mechanisms involved in GxE interactions, and then discuss epigenetic and neurodevelopmental features of SZ based on available information from genetics, epigenetics, epidemiology, neuroscience, and clinical research. We argue that epigenetic model of SZ provides a framework to integrate a variety of diverse empirical data into a powerful etiopathogenetic synthesis. The promising future of this model is the possibility to develop truly specific prevention and treatment strategies for SZ.
Muehlenkamp, Jennifer J; Bagge, Courtney L; Tull, Matthew T; Gratz, Kim L
Despite research documenting a strong association between emotion dysregulation and nonsuicidal self-injury (NSSI), the moderators of this association have received little attention. Thus, it remains unclear why some individuals with heightened emotion dysregulation engage in NSSI and others do not. Body regard (i.e., how one perceives, experiences, and cares for the body) may be one such moderator, explaining the risk for NSSI among some individuals with emotion dysregulation. The current study used structural equation modeling within a sample of 398 undergraduates (26% reporting NSSI, mean frequency = 25.16, SD = 40.5) to test the interactive effect of emotion dysregulation and body regard on NSSI frequency when controlling for negative affect and borderline personality disorder symptoms. The interaction model provided a strong fit to the data and showed that emotion regulation was associated with NSSI only when low levels of body regard were present. Results suggest that body regard may be important to understanding who engages in NSSI within the context of emotion dysregulation. Possible mechanisms underlying the interaction between body regard and emotion dysregulation are discussed along with treatment and prevention implications.
Herts, Kate L; McLaughlin, Katie A; Hatzenbuehler, Mark L
Exposure to stress is associated with a wide range of internalizing and externalizing problems in adolescents, including aggressive behavior. Extant research examining mechanisms underlying the associations between stress and youth aggression has consistently identified social information processing pathways that are disrupted by exposure to violence and increase risk of aggressive behavior. In the current study, we use longitudinal data to examine emotion dysregulation as a potential mechanism linking a broader range of stressful experiences to aggressive behavior in a diverse sample of early adolescents (N = 1065). Specifically, we examined the longitudinal associations of peer victimization and stressful life events with emotion dysregulation and aggressive behavior. Structural equation modeling was used to create latent constructs of emotion dysregulation and aggression. Both stressful life events and peer victimization predicted subsequent increases in emotion dysregulation over a 4-month period. These increases in emotion dysregulation, in turn, were associated with increases in aggression over the subsequent 3 months. Longitudinal mediation models showed that emotion dysregulation mediated the relationship of both peer victimization (z = 2.35, p = 0.019) and stressful life events (z = 2.32, p = 0.020) with aggressive behavior. Increasing the use of adaptive emotion regulation strategies is an important target for interventions aimed at preventing the onset of adolescent aggressive behavior.
Roberts, S B; Wootton, E; De Ferrari, L; Albagha, O M; Salter, D M
A variety of osteoarticular conditions possess an underlying genetic aetiology. Large-scale genome-wide association studies have identified several genetic loci associated with osteoarticular conditions, but were unable to fully account for their estimated heritability. Epigenetic modifications including DNA methylation, histone modification, nucleosome positioning, and microRNA expression may help account for this incomplete heritability. This articles reviews insights from epigenetic studies in osteoarticular diseases, focusing on osteoarthritis, but also examines recent advances in rheumatoid arthritis, osteoporosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, and sarcoma. Genome-wide methylation studies are permitting identification of novel candidate genes and molecular pathways, and the pathogenic mechanisms with altered methylation status are beginning to be elucidated. These findings are gradually translating into improved understanding of disease pathogenesis and clinical applications. Functional studies in osteoarthritis, rheumatoid arthritis, and SLE are now identifying downstream molecular alterations that may confer disease susceptibility. Epigenetic markers are being validated as prognostic and therapeutic disease biomarkers in sarcoma, and clinical trials of hypomethylating agents as treatments for sarcoma are being conducted. In concert with advances in throughput and cost-efficiency of available technologies, future epigenetic research will enable greater characterisation and treatment for both common and rare osteoarticular diseases.
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 Recently, there has been tremendous progress in characterizing the transcriptional network regulating hESCs (MacArthur et al., 2009; Loh et al., 2011, including those signaling events mediated by Oct4, Nanog and Sox2. There is growing interest in the epigenetic machinery involved in hESC self-renewal and differentiation. In general, epigenetic regulation includeschromatin reorganization, DNA modification and histone modification, which are not directly related to alterations in DNA sequences. Various protein complexes, includingPolycomb, trithorax, NuRD, SWI/SNF andOct4, have been shown to play critical roles in epigenetic control of hESC maintenance and differentiation. Hence, we will formally review recent advances in unraveling the multifaceted role of epigenetic regulation in hESC self-renewal and induced differentiation, particularly with respect to chromatin remodeling and DNA methylation events. Unraveling the molecular mechanisms underlying the maintenance/differentiation of hESCs and reprogramming of somatic cells will greatly strengthen our capacity to generate various types of cells to treat human diseases.
Vilahur, Nadia; Vahter, Marie; Broberg, Karin
Prenatal exposure to the highly toxic and common pollutant cadmium has been associated with adverse effects on child health and development. However, the underlying biological mechanisms of cadmium toxicity remain partially unsolved. Epigenetic disruption due to early cadmium exposure has gained attention as a plausible mode of action, since epigenetic signatures respond to environmental stimuli and the fetus undergoes drastic epigenomic rearrangements during embryogenesis. In the current review, we provide a critical examination of the literature addressing prenatal cadmium exposure and epigenetic effects in human, animal, and in vitro studies. We conducted a PubMed search and obtained eight recent studies addressing this topic, focusing almost exclusively on DNA methylation. These studies provide evidence that cadmium alters epigenetic signatures in the DNA of the placenta and of the newborns, and some studies indicated marked sexual differences for cadmium-related DNA methylation changes. Associations between early cadmium exposure and DNA methylation might reflect interference with de novo DNA methyltransferases. More studies, especially those including environmentally relevant doses, are needed to confirm the toxicoepigenomic effects of prenatal cadmium exposure and how that relates to the observed health effects of cadmium in childhood and later life.
Wiklund, Erik Digman
and confirming transcriptional start sites can be difficult. Epigenetics, gene regulatory and DNA modification mechanisms not involving a change to the primary sequence, have been implied in the regulation of a number of miRNA loci. Both epigenetic and miRNA signatures are broadly altered in cancer......, and are thought to play essential roles in cancer etiology and progression. Here, we aimed to identify epigenetic miRNA deregulation in bladder and oral carcinoma, and to develop a robust approach to epigenetic miRNA prediction and detection. In addition, non-canonical epigenetic functions directed by a nuclear...... miRNA were investigated. In summary, we report that the miR-200 family and miR-205 are coordinately epigenetically regulated in a variety of cell lines, tumors and normal tissues. MiR-200c expression is correlated with bladder cancer disease progression, and miR-375 levels in oral rinse can...
Rajender, Singh; Avery, Kelsey; Agarwal, Ashok
Epigenetic modifications characterized by DNA methylation, histone modifications, and chromatin remodeling are important regulators in a number of biological processes, including spermatogenesis. Several genes in the testes are regulated through epigenetic mechanisms, indicating a direct influence of epigenetic mechanisms on the process of spermatogenesis. In the present article, we have provided a comprehensive review of the epigenetic processes in the testes, correlation of epigenetic aberrations with male infertility, impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations in assisted reproduction. The literature review suggested a significant impact of epigenetic aberrations (epimutations) on spermatogenesis, and this could lead to male infertility. Epimutations (often hypermethylation) in several genes, namely MTHFR, PAX8, NTF3, SFN, HRAS, JHM2DA, IGF2, H19, RASGRF1, GTL2, PLAG1, D1RAS3, MEST, KCNQ1, LIT1, and SNRPN, have been reported in association with poor semen parameters or male infertility. Environmental toxins/drugs may affect fertility via epigenetic modifications. For example, 5-aza-2'-deoxycytidine, an anticancer agent, causes a decrease in global DNA methylation that leads to altered sperm morphology, decreased sperm motility, decreased fertilization capacity, and decreased embryo survival. Similarly, Endocrine disruptors, such as methoxychlor (an estrogenic pesticide) and vinclozolin (an anti-androgenic fungicide) have been found by experiments on animals to affect epigenetic modifications that may cause spermatogenic defects in subsequent generations. Assisted reproduction procedures that have been considered rather safe, are now being implicated in inducing epigenetic changes that could affect fertility in subsequent generations. Techniques such as intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI) may increase the incidence of imprinting disorders and
Epigenetic mechanisms have been the focus of intensive research. De Marinis et al. demonstrated that high glucose levels exert stimulatory effects on activation histone marks, leading to the upregulation of thioredoxin-interacting protein (TXNIP) gene expression, which is proinflammatory. They also showed that the effect was reversed by the inhibition of histone acetyltransferase, suggesting a new therapeutic approach for improving diabetic kidney disease. Epigenetic changes are memorized as epigenetic memory that could exacerbate diabetic complications.
Brazel, Ailbhe Jane; Vernimmen, Douglas
Over the past 30 years, a plethora of pathogenic mutations affecting enhancer regions and epigenetic regulators have been identified. Coupled with more recent genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) implicating major roles for regulatory mutations in disease, it is clear that epigenetic mechanisms represent important biomarkers for disease development and perhaps even therapeutic targets. Here, we discuss the diversity of disease-causing mutations in enhancers and epigenetic regulators, with a particular focus on cancer.
Teodora Ribarska; Klaus-Marius Bastian; Annemarie Koch; Wolfgang A Schulz
Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation,enhancer of zeste homologue 2 (EZH2)overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer.DNA methylation,EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes.Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes,expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2).A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms.Instead,selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes,which might function in the prostate to limit cell growth induced viathe PI3K/Akt pathway,modulate androgen responses and regulate differentiation.Whereas dysregulation of IG F2 may constitute an early change in prostate carcinogenesis,inactivation of this imprinted gene network is rather associated with cancer progression.
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.
Pozharny, Yevgeniya; Lambertini, Luca; Clunie, Garfield; Ferrara, Lauren; Lee, Men-Jean
Epigenetics refers to structural modifications to genes that do not change the nucleotide sequence itself but instead control and regulate gene expression. DNA methylation, histone modification, and RNA regulation are some of the mechanisms involved in epigenetic modification. Epigenetic changes are believed to be a result of changes in an organism's environment that result in fixed and permanent changes in most differentiated cells. Some environmental changes that have been linked to epigenetic changes include starvation, folic acid, and various chemical exposures. There are periods in an organism's life cycle in which the organism is particularly susceptible to epigenetic influences; these include fertilization, gametogenesis, and early embryo development. These are also windows of opportunity for interventions during the reproductive life cycle of women to improve maternal-child health. New data suggest that epigenetic influences might be involved in the regulation of fetal development and the pathophysiology of adult diseases such as cancer, diabetes, obesity, and neurodevelopmental disorders. Various epigenetic mechanisms may also be involved in the pathogenesis of preeclampsia and intrauterine growth restriction. Additionally, environmental exposures are being held responsible for causing epigenetic changes that lead to a disease process. Exposure to heavy metals, bioflavonoids, and endocrine disruptors, such as bisphenol A and phthalates, has been shown to affect the epigenetic memory of an organism. Their long-term effects are unclear at this point, but many ongoing studies are attempting to elucidate the pathophysiological effects of such gene-environment interactions. (c) 2010 Mount Sinai School of Medicine.
Sexton, Tom; Yaffe, Eitan
Despite a growing understanding of how epigenetic marks such as histone modifications locally modify the activity of the chromatin with which they are associated, we know little about how marked regions on different parts of the genome are able to intercommunicate to effect regulation of gene expression programs. Recent advances in methods that systematically map pairwise chromatin interactions have uncovered important principles of chromosome folding, which are tightly linked to the epigenetic mark profiles and, hence, functional state of the underlying chromatin fiber.
Ho, Emily; Laura M Beaver; Williams, David E.; DASHWOOD, RODERICK H.
The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, ...
Yu, Li; Wu, YiMing; Wu, Bai-Lin
Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.
Lind, Mads Vendelbo
Background: Dysregulation of one-carbon metabolism (OCM) is related to metabolic syndrome (MetS) through various mechanisms including epigenetics. Diet plays a central role in ensuring normal OCM regulation by supplying multiple nutrients. Foods such as whole grains and fish have been proposed...... acid (EPA) and docosahexaenoic acid (DHA) which might also play a role in OCM regulation and epigenetics. Aim: This PhD thesis investigates the role of diet in OCM regulation and the potential association between OCM and MetS. We further investigated whether a dietary intervention with high whole grain...... intake can affect OCM metabolites in plasma. Finally, we explored whether a fish oil supplement can induce epigenetic changes and whether these are related to MetS features. Methods: In two cross-sectional studies using the 3G-cohort, we investigated associations between plasma OCM metabolites, s...
W Watson, Gregory; M Beaver, Laura; E Williams, David; H Dashwood, Roderick; Ho, Emily
Epidemiological evidence has demonstrated a reduced risk of prostate cancer associated with cruciferous vegetable intake. Follow-up studies have attributed this protective activity to the metabolic products of glucosinolates, a class of secondary metabolites produced by crucifers. The metabolic products of glucoraphanin and glucobrassicin, sulforaphane, and indole-3-carbinol respectively, have been the subject of intense investigation by cancer researchers. Sulforaphane and indole-3-carbinol inhibit prostate cancer by both blocking initiation and suppressing prostate cancer progression in vitro and in vivo. Research has largely focused on the anti-initiation and cytoprotective effects of sulforaphane and indole-3-carbinol through induction of phases I and II detoxification pathways. With regards to suppressive activity, research has focused on the ability of sulforaphane and indole-3-carbinol to antagonize cell signaling pathways known to be dysregulated in prostate cancer. Recent investigations have characterized the ability of sulforaphane and indole-3-carbinol derivatives to modulate the activity of enzymes controlling the epigenetic status of prostate cancer cells. In this review, we will summarize the well-established, "classic" non-epigenetic targets of sulforaphane and indole-3-carbinol, and highlight more recent evidence supporting these phytochemicals as epigenetic modulators for prostate cancer chemoprevention.
Duarte, Julio D
Epigenetics describes heritable alterations of gene expression that do not involve DNA sequence variation and are changeable throughout an organism's lifetime. Not only can epigenetic status influence drug response, but it can also be modulated by drugs. In this review, the three major epigenetic mechanisms are described: covalent DNA modification, histone protein modification, and regulation by noncoding RNA. Further, this review describes how drug therapy can influence, and be influenced by, these mechanisms. Drugs with epigenetic mechanisms are already in use, with many more likely to be approved within the next few years. As the understanding of epigenetic processes improves, so will the ability to use these data in the clinic to improve patient care. © 2013 Pharmacotherapy Publications, Inc.
Lötsch, Jörn; Schneider, Gisbert; Reker, Daniel; Parnham, Michael J; Schneider, Petra; Geisslinger, Gerd; Doehring, Alexandra
Epigenetic effects are exerted by a variety of factors and evidence increases that common drugs such as opioids, cannabinoids, valproic acid, or cytostatics may induce alterations in DNA methylation patterns or histone conformations. These effects occur via chemical structural interactions with epigenetic enzymes, through interactions with DNA repair mechanisms. Computational predictions indicate that one-twentieth of all drugs might potentially interact with human histone deacetylase, which was prospectively experimentally verified for the compound with the highest predicted interaction probability. These epigenetic effects add to wanted and unwanted drug effects, contributing to mechanisms of drug resistance or disease-related and unrelated phenotypes. Because epigenetic changes might be transmitted to offspring, the need for reliable and cost-effective epigenetic screening tools becomes acute.
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.
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.
Herrera, Carlos M; Medrano, Mónica; Bazaga, Pilar
Despite the recent upsurge of interest on natural epigenetic variation of nonmodel organisms, factors conditioning the spatial structure of epigenetic diversity in wild plant populations remain virtually unexplored. We propose that information on processes shaping natural epigenetic variation can be gained using the spatial structure of genetic diversity as null model. Departures of epigenetic isolation-by-distance (IBD) patterns from genetic IBD patterns for the same sample, particularly differences in slope of similarity-distance regressions, will reflect the action of factors that operate specifically on epigenetic variation, including imperfect transgenerational inheritance and responsiveness to environmental factors of epigenetic marks. As a proof of concept, we provide a comparative analysis of spatial genetic and epigenetic structure of 200 mapped individuals of the perennial herb Helleborus foetidus. Plants were fingerprinted using nuclear microsatellites, amplified fragment length polymorphisms (AFLP) and methylation-sensitive AFLP markers. Expectations from individual-level IBD patterns were tested by means of kinship-distance regressions. Both genetic and epigenetic similarity between H. foetidus individuals conformed to theoretical expectations under individual-level IBD models. Irrespective of marker type, there were significant negative linear relationships between the kinship coefficient for plant pairs and their spatial separation. Regression slopes were significantly steeper for epigenetic markers. Epigenetic similarity between individuals was much greater than genetic similarity at shortest distances, such epigenetic 'kinship excess' tending to decrease as plant separation increased. Results suggest that moderate-to-high heritability and responsiveness to local environments are major drivers of epigenetic spatial structure in H. foetidus, and illustrate the heuristic value of comparing genetic and epigenetic spatial structure for formulating
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 tran
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
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 confer
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.
Kellermann, Natan Pf
The Holocaust left its visible and invisible marks not only on the survivors, but also on their children. Instead of numbers tattooed on their forearms, however, they may have been marked epigenetically with a chemical coating upon their chromosomes, which would represent a kind of biological memory of what the parents experienced. as a result, some suffer from a general vulnerability to stress while others are more resilient. Previous research assumed that such transmission was caused by environmental factors, such as the parents' childrearing behavior. New research, however, indicates that these transgenerational effects may have been also (epi) genetically transmitted to their children. Integrating both hereditary and environmental factors, epigenetics adds a new and more comprehensive psychobiological dimension to the explanation of transgenerational transmission of trauma. Specifically, epigenetics may explain why latent transmission becomes manifest under stress. a general theoretical overview of epigenetics and its relevance to research on trauma transmission is presented.
The methylazoxymethanol acetate rat model: molecular and epigenetic effect in the developing prefrontal cortex: An Editorial Highlight for 'Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia' on doi: 10.1111/jnc.14101.
Zhu, Xiyu; Gomes, Felipe V; Grace, Anthony A
This Editorial highlights an article by Gulchina and colleagues in the current issue of the Journal of Neurochemistry, in which the authors describe molecular and epigenetic changes in the developing prefrontal cortex of the rats exposed to methylazoxymethanol acetate (MAM). They found an NMDAR hypofunction present in the prefrontal cortex of juvenile MAM rats which was associated with abnormal epigenetic regulation of the Grin2b gene. These changes may be related to early cognitive impairments observed in MAM rats and schizophrenia patients. © 2017 International Society for Neurochemistry.
Zielinski, Daniel C.; Filipp, F. V.; Bordbar, A.
Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...... dysregulated by drugs are linked to the development of side effects. We show such dysregulated metabolic pathways contain genes with sequence variants affecting side effect incidence, play established roles in pathophysiology, have significantly altered activity in corresponding diseases, are susceptible...... to metabolic inhibitors and are effective targets for therapeutic nutrient supplementation. Our results indicate that metabolic dysregulation represents a common mechanism underlying side effect pathogenesis that is distinct from the role of metabolism in drug clearance. We suggest that elucidating...
Qazi, Talal Jamil; Quan, Zhenzhen; Mir, Asif; Qing, Hong
Research over the years has shown that causes of Alzheimer's disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer's disease (AD), late-onset Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and autosomal dominant Alzheimer's disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.
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.
Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significan...
Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko
Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191
Rocchi, Giordana; Serio, Valentina; Carluccio, Giuseppe Mattia; Marini, Isabella; Meuti, Valentina; Zaccagni, Michela; Giacchetti, Nicoletta; Aceti, Franca
Recently, new findings in epigenetic science switched the focus from the observation of physiological intragenomic dynamics to the idea of an environmental co-construction of phenotypic expression. In psichodynamic field, objectual relations and attachement theoreticians emphasized the interpersonal dimension of individual development, focusing the attention on the relational matrix of self organization. The construction of stable affective-behavioral traits throughout different parenting styles has actually found a coincidence in ethological studies, which have explored the epigenetic processes underlying the relationship between caregiving and HPA stress responsiveness. An adequate parenting style seems to support affective regulation throughout psychobiological hidden moderators, which would tend to rebalance the physiological systems homeostasis; an unconfident attachment style would promote, on the other hand, the allostatic load rise. Sites of longlife epigenetic susceptibility have also been identified in humans; although associated with risk of maladaptive developing in adverse environmental conditions, they seem to confer protection under favorable conditions. This persisting possibility of reorganization of stable traits throughout lifetime, which seems to be activated by a relevant environmental input, grant to significant relationships, and to therapeutical one as well, an implicit reconditioning potential which could result into the configuration of new stable affective-behavioral styles.
Patalano, Solenn; Hore, Timothy A; Reik, Wolf; Sumner, Seirian
Epigenetic modifications are ancient and widely utilised mechanisms that have been recruited across fungi, plants and animals for diverse but fundamental biological functions, such as cell differentiation. Recently, a functional DNA methylation system was identified in the honeybee, where it appears to underlie queen and worker caste differentiation. This discovery, along with other insights into the epigenetics of social insects, allows provocative analogies to be drawn between insect caste differentiation and cellular differentiation, particularly in mammals. Developing larvae in social insect colonies are totipotent: they retain the ability to specialise as queens or workers, in a similar way to the totipotent cells of early embryos before they differentiate into specific cell lineages. Further, both differentiating cells and insect castes lose phenotypic plasticity by committing to their lineage, losing the ability to be readily reprogrammed. Hence, a comparison of the epigenetic mechanisms underlying lineage differentiation (and reprogramming) between cells and social insects is worthwhile. Here we develop a conceptual model of how loss and regain of phenotypic plasticity might be conserved for individual specialisation in both cells and societies. This framework forges a novel link between two fields of biological research, providing predictions for a unified approach to understanding the molecular mechanisms underlying biological complexity.
Chou, Hsueh-Fen; Kao, Chien-Huei; Gau, Meei-Ling
Epigenetics is a field of biomedicine that expanded tremendously during the 1980s. Epigenetics is the study of heritable changes in gene expression independent of underlying DNA (DeoxyriboNucleic Acid) sequence, which not only affect this generation but will be passed to subsequent generations. Although conception is the critical moment for making decisions regarding gene mapping and fetal health, studies have shown that perinatal nursing care practices also affect the genetic remodeling processes and the subsequent health of the mother and her offspring. To optimize maternal-infant and the offspring health, it is important to ensure that the new mother get adequate nutrition, reduce stress levels, adopt gentle birth practices, facilitate exclusive breastfeeding, and avoid contacting toxic substances.
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.
Luciana Romina Frick
Full Text Available Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.
Lavender, Jason M; Wonderlich, Stephen A; Peterson, Carol B; Crosby, Ross D; Engel, Scott G; Mitchell, James E; Crow, Scott J; Smith, Tracey L; Klein, Marjorie H; Goldschmidt, Andrea B; Berg, Kelly C
The goal of this study was to examine associations between dimensions of emotion dysregulation and eating disorder (ED) symptoms in bulimia nervosa (BN). This investigation used baseline data from a BN treatment study that included 80 adults (90% women) with full or subthreshold BN. Participants completed the Difficulties in Emotion Regulation Scale (DERS) and the Eating Disorders Examination interview. The Eating Disorders Examination global score was significantly correlated with the DERS total score, as well as several DERS subscales: nonacceptance, impulse and strategies. Further, the DERS goals subscale was found to be uniquely associated with frequency of purging and driven exercise, although none of the subscales were associated with frequency of objective binge eating. Findings indicate that emotion dysregulation is associated with ED symptoms in BN, suggesting the utility of interventions that address emotion regulation skills deficits in the treatment of the disorder.
Mazzio, Elizabeth A; Soliman, Karam F A
All terrestrial life is influenced by multi-directional flows of information about its environment, enabling malleable phenotypic change through signals, chemical processes, or various forms of energy that facilitate acclimatization. Billions of biological co-inhabitants of the earth, including all plants and animals, collectively make up a genetic/epigenetic ecosystem by which adaptation/survival (inputs and outputs) are highly interdependent on one another. As an ecosystem, the solar system, rotation of the planets, changes in sunlight, and gravitational pull influence cyclic epigenetic transitions and chromatin remodeling that constitute biological circadian rhythms controlling senescence. In humans, adverse environmental conditions such as poverty, stress, alcohol, malnutrition, exposure to pollutants generated from industrialization, man-made chemicals, and use of synthetic drugs can lead to maladaptive epigenetic-related illnesses with disease-specific genes being atypically activated or silenced. Nutrition and dietary practices are one of the largest facets in epigenetic-related metabolism, where specific "epi-nutrients" can stabilize the genome, given established roles in DNA methylation, histone modification, and chromatin remodeling. Moreover, food-based "epi-bioactive" constituents may reverse maladaptive epigenetic patterns, not only prior to conception and during fetal/early postnatal development but also through adulthood. In summary, in contrast to a static genomic DNA structure, epigenetic changes are potentially reversible, raising the hope for therapeutic and/or dietary interventions that can reverse deleterious epigenetic programing as a means to prevent or treat major illnesses.
Bossdorf, Oliver; Zhang, Yuanye
Until a few years ago, epigenetics was a field of research that had nothing to do with ecology and that virtually no ecologist had ever heard of. This is now changing, as more and more ecologists learn about epigenetic processes and their potential ecological and evolutionary relevance, and a new research field of ecological epigenetics is beginning to take shape. One question that is particularly intriguing ecologists is to what extent epigenetic variation is an additional, and hitherto overlooked, source of natural variation in ecologically important traits. In this issue of Molecular Ecology, Herrera & Bazaga (2011) provide one of the first attempts to truly address this question in an ecological setting. They study variation of DNA methylation in a wild population of the rare, long-lived violet Viola cazorlensis, and they use these data to explore interrelations between environmental, genetic and epigenetic variation, and in particular the extent to which these factors are related to long-term differences in herbivore damage among plants. They find substantial epigenetic variation among plant individuals. Interestingly, this epigenetic variation is significantly correlated with long-term differences in herbivory, but only weakly with herbivory-related DNA sequence variation, which suggests that besides habitat, substrate and genetic variation, epigenetic variation may be an additional, and at least partly independent, factor influencing plant–herbivore interactions in the field. Although the study by Herrera & Bazaga (2011) raises at least as many new questions as it answers, it is a pioneering example of how epigenetics can be incorporated into ecological field studies, and it illustrates the value and potential novel insights to be gained from such efforts.
Nicolia, Vincenzina; Lucarelli, Marco; Fuso, Andrea
Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation.
Recent advances in epigenetics have had tremendous impact on our thinking and understanding of biological phenomena and the impact of environmental stressors on complex diseases, notably cancer. Environmental and lifestyle factors are thought to be implicated in the development of a wide range of human cancers by eliciting epigenetic changes, however, the underlying mechanisms remain poorly understood. Epigenetic mechanisms can be viewed as an interface between the genome and environmental influence, therefore aberrant epigenetic events associated with environmental stressors and factors in the cell microenvironment are likely to play an important role in the onset and progression of different human malignancies. At the cellular level, aberrant epigenetic events influence critical cellular events (such as gene expression, carcinogen detoxification, DNA repair, and cell cycle), which are further modulated by risk factor exposures and thus may define the severity/subtype of cancer. This review summarizes recent progress in our understanding of the epigenetic mechanisms through which environmental stressors and endogenous factors may promote tumor development and progression.
Epigenetic programming is likely to be an important mechanism underlying the lasting influence of the developmental environment on lifelong health, a concept known as the Developmental Origins of Health and Disease (DOHaD). DNA methylation, posttranslational histone protei n modifications, noncoding RNAs and recruited protein complexes are elements of the epigenetic regulation of gene transcription. These heritable but reversible changes in gene function are dynamic and labile during specific stages of the reproductive cycle and development. Epigenetic marks may be maintained throughout an individual's lifespan and can alter the life-long risk of disease; the nature of these epigenetic marks and their potential alteration by environmental factors is an area of active research. This chapter provides an overview of epigenetic regulation, particularly as it occurs as an essential component of embryo-fetal development. In this chapter we will present key features of DNA methylation and histone protein modifications, including the enzymes involved and the effects of these modifications on gene transcription. We will discuss the interplay of these dynamic modifications and the emerging role of noncoding RNAs in epigenetic gene regulation.
Mukherjee, Krishnendu; Twyman, Richard M; Vilcinskas, Andreas
Epigenetic inheritance refers to changes in gene expression that are heritable across generations but are not caused by changes in the DNA sequence. Many environmental factors are now known to cause epigenetic changes, including the presence of pathogens, parasites, harmful chemicals and other stress factors. There is increasing evidence that transcriptional reprogramming caused by epigenetic modifications can be passed from parents to offspring. Indeed, diseases such as cancer can occur in the offspring due to epigenetically-inherited gene expression profiles induced by stress experienced by the parent. Empirical studies to investigate the role of epigenetics in trans-generational gene regulation and disease require appropriate model organisms. In this review, we argue that selected insects can be used as models for human diseases with an epigenetic component because the underlying molecular mechanisms (DNA methylation, histone acetylation and the expression of microRNAs) are evolutionarily conserved. Insects offer a number of advantages over mammalian models including ethical acceptability, short generation times and the potential to investigate complex interacting parameters such as fecundity, longevity, gender ratio, and resistance to pathogens, parasites and environmental stress.
Millan, Mark J
Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.
Explanations for biological evolution in terms of changes in gene frequencies refer to outcomes rather than process. Integrating epigenetic studies with older evolutionary theories has drawn attention to the ways in which evolution occurs. Adaptation at the level of the gene is givingway to adaptation at the level of the organism and higher-order assemblages of organisms. These ideas impact on the theories of how cooperation might have evolved. Two of the theories, i.e. that cooperating individuals are genetically related or that they cooperate for self-interested reasons, have been accepted for a long time. The idea that adaptation takes place at the level of groups is much more controversial. However, bringing together studies of development with those of evolution is taking away much of the heat in the debate about the evolution of group behaviour.
Explanations for biological evolution in terms of changes in gene frequencies refer to outcomes rather than process. Integrating epigenetic studies with older evolutionary theories has drawn attention to the ways in which evolution occurs. Adaptation at the level of the gene is givingway to adaptation at the level of the organism and higher-order assemblages of organisms. These ideas impact on the theories of how cooperation might have evolved. Two of the theories, i.e. that cooperating individuals are genetically related or that they cooperate for self-interested reasons, have been accepted for a long time. The idea that adaptation takes place at the level of groups is much more controversial. However, bringing together studies of development with those of evolution is taking away much of the heat in the debate about the evolution of group behaviour.
Thomas A. Milne
Full Text Available Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis.
Full Text Available Abstract Background Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis. Results We show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts. Conclusions This study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.
Ballabio, Erica; Milne, Thomas A., E-mail: firstname.lastname@example.org [MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital Headington, Oxford OX3 9DS (United Kingdom)
Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis.
Wang, Qian; Gosik, Kirk; Xing, Sujuan; Jiang, Libo; Sun, Lidan; Chinchilli, Vernon M.; Wu, Rongling
Epigenetic reprogramming is thought to play a critical role in maintaining the normal development of embryos. How the methylation state of paternal and maternal genomes regulates embryogenesis depends on the interaction and coordination of the gametes of two sexes. While there is abundant research in exploring the epigenetic interactions of sperms and oocytes, a knowledge gap exists in the mechanistic quantitation of these interactions and their impact on embryo development. This review aims at formulating a modeling framework to address this gap through the integration and synthesis of evolutionary game theory and the latest discoveries of the epigenetic control of embryo development by next-generation sequencing. This framework, named epigenetic game theory or epiGame, views embryogenesis as an ecological system in which two highly distinct and specialized gametes coordinate through either cooperation or competition, or both, to maximize the fitness of embryos under Darwinian selection. By implementing a system of ordinary differential equations, epiGame quantifies the pattern and relative magnitude of the methylation effects on embryogenesis by the mechanisms of cooperation and competition. epiGame may gain new insight into reproductive biology and can be potentially applied to design personalized medicines for genetic disorder intervention.
Paz-Priel, Ido; Cooke, David W.; Chen, Allen R
Patients with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor syndrome have poor long-term outcomes. We report a patient who was treated successfully with high-dose cyclophosphamide immunoablation. This experience offers a novel therapeutic approach and an indirect insight into the underlying pathogenesis of this syndrome.
Evans, Gary W; Kim, Pilyoung
A massive literature documents the inverse association between poverty or low socioeconomic status and health, but little is known about the mechanisms underlying this robust relation. We examined longitudinal relations between duration of poverty exposure since birth, cumulative risk exposure, and physiological stress in two hundred seven 13-year-olds. Chronic stress was assessed by basal blood pressure and overnight cortisol levels; stress regulation was assessed by cardiovascular reactivity to a standard acute stressor and recovery after exposure to this stressor. Cumulative risk exposure was measured by multiple physical (e.g., substandard housing) and social (e.g., family turmoil) risk factors. The greater the number of years spent living in poverty, the more elevated was overnight cortisol and the more dysregulated was the cardiovascular response (i.e., muted reactivity). Cardiovascular recovery was not affected by duration of poverty exposure. Unlike the duration of poverty exposure, concurrent poverty (i.e., during adolescence) did not affect these physiological stress outcomes. The effects of childhood poverty on stress dysregulation are largely explained by cumulative risk exposure accompanying childhood poverty.
Full Text Available Autism spectrum disorder (ASD is a neurodevelopmental disorder characterized by an impaired social communication skill and often results in repetitive, stereotyped behavior which is observed in children during the first few years of life. Other characteristic of this disorder includes language disabilities, difficulties in sensory integration, lack of reciprocal interactions and in some cases, cognitive delays. One percentage of the general population is affected by ASD and is four times more common in boys than girls. There are hundreds of genes, which has been identified to be associated with ASD etiology. However it remains difficult to comprehend our understanding in defining the genetic architecture necessary for complete exposition of its pathophysiology. Seeing the complexity of the disease, it is important to adopt a multidisciplinary approach which should not only focus on the “genetics” of autism but also on epigenetics, transcriptomics, immune system disruption and environmental factors that could all impact the pathogenesis of the disease. As environmental factors also play a key role in regulating the trigger of ASD, the role of chromatin remodeling and DNA methylation has started to emerge. Such epigenetic modifications directly link molecular regulatory pathways and environmental factors, which might be able to explain some aspects of complex disorders like ASD. The present review will focus on the role of epigenetic regulation in defining the underlying cause for ASD
Full Text Available The term ‘junk DNA’ has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterchromatinised resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide and tetranucleotide repeats. The association between repetitive regions and disease was emphasised following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy’s disease and fragile X syndrome of mental retardation (FRAXA in 1991. In this review we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.
Seelan, Ratnam S; Mukhopadhyay, Partha; Pisano, M Michele; Greene, Robert M
Orofacial clefts occur with a frequency of 1 to 2 per 1000 live births. Cleft palate, which accounts for 30% of orofacial clefts, is caused by the failure of the secondary palatal processes--medially directed, oral projections of the paired embryonic maxillary processes--to fuse. Both gene mutations and environmental effects contribute to the complex etiology of this disorder. Although much progress has been made in identifying genes whose mutations are associated with cleft palate, little is known about the mechanisms by which the environment adversely influences gene expression during secondary palate development. An increasing body of evidence, however, implicates epigenetic processes as playing a role in adversely influencing orofacial development. Epigenetics refers to inherited changes in phenotype or gene expression caused by processes other than changes in the underlying DNA sequence. Such processes include, but are not limited to, DNA methylation, microRNA effects, and histone modifications that alter chromatin conformation. In this review, we describe our current understanding of the possible role epigenetics may play during development of the secondary palate. Specifically, we present the salient features of the embryonic palatal methylome and profile the expression of numerous microRNAs that regulate protein-encoding genes crucial to normal orofacial ontogeny.
Epigenetic programming is an important mechanism underlying the Developmental Origins of Health and Disease (DOHaD). Much of the research in this area has focused on maternal nutrition. Parental smoking has emerged as a prime example of how exposure to environmental toxicants during the preconceptional and in utero periods can have long-term effects on offspring health, and the role of the epigenome in these effects. Maternal smoking and exposure to second-hand smoke during pregnancy result in lower birth weight of offspring, and there is now clear evidence that these offspring are at elevated risk for overweight/obesity, type-2 diabetes, respiratory effects during adolescence and adulthood, and may be programmed for increased risk of nicotine addiction. Epigenetic analyses of placenta, cord blood and offspring buccal cells have consistently revealed altered DNA methylation of genes involved in developmental processes and xenobiotic metabolism, and these epigenetic changes are persistent. Animal studies with cigarette smoke and nicotine support these findings. Paternal preconceptional smoking has been positively related to childhood cancers, potentially linked to changes in the sperm epigenome. Germ cell specification and preimplantation development are periods of widespread erasure and reprogramming of DNA methylation, and as such are likely to be sensitive periods for environmental effects on the epigenome. Exposure to tobacco smoke during gametogenesis and in
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
Marcus Vallaster; Caroline Dacwag Vallaster; Sean M. Wu
During mammalian development,cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific transcription factors (TFs) and their meticulous control on an epigenetic level.In this review,we detail how cardiacspecific TFs function in concert with nucleosome remodeling and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation,or epithelial to mesenchymal transition (EMT),for instance.We provide examples of how several cardiac TFs,such as Nkx2.5,WHSC1,Tbx5,and Tbx1,which are associated with developmental and congenital heart defects,are required for the recruitment of histone modifiers,such as Jarid2,p300,and Ash21,and components of ATP-dependent remodeling enzymes like Brg1,Baf60c,and Baf180.Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks,indicating that the precise regulation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers.Furthermore,we speculate that an epigenetic signature,comprised of TF occupancy,histone modifications,and overall chromatin organization,is an underlying mechanism that governs cardiac morphogenesis and disease.
Zhang, Jian; Choudhury, Mahua
Exposure to environmental chemicals can perturb an individual's metabolic set point, especially during critical periods of development, and as a result increase his or her propensity towards obesity that is manifested later in life and possibly in successive generations. We hypothesized that benzyl butyl phthalate (BBP), a widespread endocrine disruptor, may impair one important epigenetic regulator, sirtuin, in mesenchymal stem cells and induce adipogenesis. Our results showed that gene expression of two well-known adipogenic markers, aP2 and PPARγ, were significantly increased from day 2 to day 8 under 50μM BBP exposure when compared to control in C3H10T1/2 stem cells (p<0.05) and induced adipogenesis. Sirt1 gene expression was also significantly decreased at day 2, 4, 6, and 8 (p<0.05). However, Sirt7 gene expression was decreased only at day 2 and 8 (p<0.05) while other sirtuin transcriptional levels remained unaltered throughout. Furthermore, Sirt1 and Sirt3 protein expression was decreased (p<0.05) and overall protein hyperacetylation was observed at day 8. Furthermore, FOXO1 and β-catenin, Sirt1 targets and adipogenesis regulators, were hyperacetylated at day 8. PGC1α, NRF1, NRF2, and Tfam, were also significantly decreased (p<0.05). In conclusion, our study suggests for the first time that BBP, a potential epigenetic disruptor, can lead to increased adipogenesis and metabolic dysregulation by impairing vital epigenetic regulators. Copyright © 2016 Elsevier B.V. All rights reserved.
Bekdash, Rola; Zhang, Changqing; Sarkar, Dipak
Hypothalamic proopiomelanocortin (POMC) neurons, one of the major regulators of the hypothalamic-pituitary-adrenal (HPA) axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE). These effects are manifested in POMC neurons by a decrease in Pomc gene expression, a decrement in the levels of its derived peptide β-endorphin and a dysregulation of the stress response in the adult offspring. The HPA axis is a major neuroendocrine system with pivotal physiological functions and mode of regulation. This system has been shown to be perturbed by prenatal alcohol exposure. It has been demonstrated that the perturbation of the HPA axis by FAE is long-lasting and is linked to molecular, neurophysiological, and behavioral changes in exposed individuals. Recently, we showed that the dysregulation of the POMC system function by FAE is induced by epigenetic mechanisms such as hypermethylation of Pomc gene promoter and an alteration in histone marks in POMC neurons. This developmental programming of the POMC system by FAE altered the transcriptome in POMC neurons and induced a hyperresponse to stress in adulthood. These long-lasting epigenetic changes influenced subsequent generations via the male germline. We also demonstrated that the epigenetic programming of the POMC system by FAE was reversed in adulthood with the application of the inhibitors of DNA methylation or histone modifications. Thus, prenatal environmental influences, such as alcohol exposure, could epigenetically modulate POMC neuronal circuits and function to shape adult behavioral patterns. Identifying specific epigenetic factors in hypothalamic POMC neurons that are modulated by fetal alcohol and target Pomc gene could be potentially useful for the development of new therapeutic approaches to treat stress-related diseases in patients with fetal alcohol spectrum disorders.
Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M Eric; Lu, Qianjin
One of the major disappointments in human autoimmunity has been the relative failure on genome-wide association studies to provide "smoking genetic guns" that would explain the critical role of genetic susceptibility to loss of tolerance. It is well known that autoimmunity refers to the abnormal state that the dysregulated immune system attacks the healthy cells and tissues due to the loss of immunological tolerance to self-antigens. Its clinical outcomes are generally characterized by the presence of autoreactive immune cells and (or) the development of autoantibodies, leading to various types of autoimmune disorders. The etiology and pathogenesis of autoimmune diseases are highly complex. Both genetic predisposition and environmental factors such as nutrition, infection, and chemicals are implicated in the pathogenic process of autoimmunity, however, how much and by what mechanisms each of these factors contribute to the development of autoimmunity remain unclear. Epigenetics, which refers to potentially heritable changes in gene expression and function that do not involve alterations of the DNA sequence, has provided us with a brand new key to answer these questions. In the recent decades, increasing evidence have demonstrated the roles of epigenetic dysregulation, including DNA methylation, histone modification, and noncoding RNA, in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE), which have shed light on a new era for autoimmunity research. Notably, DNA hypomethylation and reactivation of the inactive X chromosome are two epigenetic hallmarks of SLE. We will herein discuss briefly how genetic studies fail to completely elucidate the pathogenesis of autoimmune diseases and present a comprehensive review on landmark epigenetic findings in autoimmune diseases, taking SLE as an extensively studied example. The epigenetics of other autoimmune diseases such as rheumatic arthritis, systemic sclerosis and primary biliary
de Groote, Marloes L.; Verschure, Pernette J.; Rots, Marianne G.
Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined D
de Groote, M.L.; Verschure, P.J.; Rots, M.G.
Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined D
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.
Full Text Available Epigenetic mechanisms, acting via chromatin organization, fix in time and space different transcriptional programs and contribute to the quality, stability, and heritability of cell-specific transcription programs. In the last years, great advances have been made in our understanding of mechanisms by which this occurs in normal subjects. However, only a small part of the complete picture has been revealed. Abnormal gene expression patterns are often implicated in the development of different diseases, and thus epigenetic studies from patients promise to fill an important lack of knowledge, deciphering aberrant molecular mechanisms at the basis of pathogenesis and diseases progression. The identification of epigenetic modifications that could be used as targets for therapeutic interventions could be particularly timely in the light of pharmacologically reversion of pathological perturbations, avoiding changes in DNA sequences. Here I discuss the available information on epigenetic mechanisms that, altered in neuromuscular disorders, could contribute to the progression of the disease.
Saccone, Valentina; Puri, Pier Lorenzo
During embryogenesis a timely and coordinated expression of different subsets of genes drives the formation of skeletal muscles in response to developmental cues. In this review, we will summarize the most recent advances on the “epigenetic network” that promotes the transcription of selective groups of genes in muscle progenitors, through the concerted action of chromatin-associated complexes that modify histone tails and microRNAs (miRNAs). These epigenetic players cooperate to establish fo...
Riya Rajan Kanherkar
Full Text Available Epigenetics has the potential to explain various biological phenomena that have heretofore defied complete explication. This review describes the various types of endogenous human developmental milestones such as birth, puberty, and menopause, as well as the diverse exogenous environmental factors that influence human health, in a chronological epigenetic context. We describe the entire course of human life from periconception to death and chronologically note all of the potential internal timepoints and external factors that influence the human epigenome. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors. During the course of human life, we are exposed to an environment that abounds with a potent and dynamic milieu capable of triggering chemical changes that activate or silence genes. There is constant interaction between the external and internal environments that is required for normal development and health maintenance as well as for influencing disease load and resistance. For example, exposure to pharmaceutical and toxic chemicals, diet, stress, exercise, and other environmental factors are capable of eliciting positive or negative epigenetic modifications with lasting effects on development, metabolism and health. These can impact the body so profoundly as to permanently alter the epigenetic profile of an individual. We also present a comprehensive new hypothesis of how these diverse environmental factors cause both direct and indirect epigenetic changes and how this knowledge can ultimately be used to improve personalized medicine.
Hauser, Marie-Theres; Aufsatz, Werner; Jonak, Claudia; Luschnig, Christian
Interest in transgenerational epigenetic inheritance has intensified with the boosting of knowledge on epigenetic mechanisms regulating gene expression during development and in response to internal and external signals such as biotic and abiotic stresses. Starting with an historical background of scantily documented anecdotes and their consequences, we recapitulate the information gathered during the last 60 years on naturally occurring and induced epialleles and paramutations in plants. We present the major players of epigenetic regulation and their importance in controlling stress responses. The effect of diverse stressors on the epigenetic status and its transgenerational inheritance is summarized from a mechanistic viewpoint. The consequences of transgenerational epigenetic inheritance are presented, focusing on the knowledge about its stability, and in relation to genetically fixed mutations, recombination, and genomic rearrangement. We conclude with an outlook on the importance of transgenerational inheritance for adaptation to changing environments and for practical applications. This article is part of a Special Issue entitled "Epigenetic control of cellular and developmental processes in plants".
Sapienza, Carmen; Issa, Jean-Pierre
The search for a connection between diet and human cancer has a long history in cancer research, as has interest in the mechanisms by which dietary factors might increase or decrease cancer risk. The realization that altering diet can alter the epigenetic state of genes and that these epigenetic alterations might increase or decrease cancer risk is a more modern notion, driven largely by studies in animal models. The connections between diet and epigenetic alterations, on the one hand, and between epigenetic alterations and cancer, on the other, are supported by both observational studies in humans as well as animal models. However, the conclusion that diet is linked directly to epigenetic alterations and that these epigenetic alterations directly increase or decrease the risk of human cancer is much less certain. We suggest that true and measurable effects of diet or dietary supplements on epigenotype and cancer risk are most likely to be observed in longitudinal studies and at the extremes of the intersection of dietary risk factors and human population variability. Careful analysis of such outlier populations is most likely to shed light on the molecular mechanisms by which suspected environmental risk factors drive the process of carcinogenesis.
Martoccio, Tiffany L; Brophy-Herb, Holly E; Maupin, Angela N; Robinson, Joann L
There is some evidence linking maternal depression, harsh parenting, and children's internal representations of attachment, yet, longitudinal examinations of these relationships and differences in the developmental pathways between boys and girls are lacking. Moderated mediation growth curves were employed to examine harsh parenting as a mechanism underlying the link between maternal depression and children's dysregulated representations using a nationally-representative, economically-vulnerable sample of mothers and their children (n = 575; 49% boys, 51% girls). Dysregulation representations were measured using the MacArthur Story Stem Battery at five years of age (M = 5.14, SD = 0.29). Harsh parenting mediated the association between early maternal depression and dysregulated representations for girls. Though initial harsh parenting was a significant mediator for boys, a stronger direct effect of maternal depression to dysregulated representations emerged over time. Results are discussed in terms of their implications for intervention efforts aimed at promoting early supportive parenting.
樊洪泓; 李廷春; 李正鹏; 林毅; 蔡永萍; 金青
The methylation-sensitive amplified polymorphism (MSAP) techniques were used to assess genetic and epigenetic variations of Dendrobium huoshanense under drought stress. Results showed that the level of global DNA methylation decreased with increasing of PEG-6000 concentrations. When the tube seedlings were treated with 5％ ,10％, 15％ of PEG-6000, the levels of DNA methylation dropped to 34.7％, 32.9％ and 30.4％, respectively,compared with that for the control group ( 37. 2％ ). There was a significantly negative correlation ( r = - 0. 998 )between PEG-6000 and DNA methylation. In contrast with the control, under stress of 5％, 10％ and 15％ PEG-6000,methylation and demethylation of DNA were 12. 02％, 12. 50％, 15.53％ and 8.39％, 8.55％ , 8.45％, respectively.The ratios of DNA methylation and demethylation, the polymorphism of DNA methylation increased gradually,accompanied with the enhancement of drought stress.%利用甲基化敏感扩增多态性(methylation-sensitive amplification polymorphism,MSAP)技术,研究不同聚乙二醇(PEG-6000)处理浓度下霍山石斛基因组DNA的甲基化水平和变化模式.结果表明:经5%、10%和15%PEG-6000处理的霍山石斛DNA甲基化比率分别为34.7%、32.9%和30.4%,均低于对照的37.2%,且甲基化水平与PEG-6000处理浓度呈显著负相关(r=-0.998).与对照相比,5%、10%和15%PEG-6000胁迫下霍山石斛基因组DNA发生甲基化变化的位点比例为12.02%、12.50%和15.53%,去甲基化位点比例为8.39%、8.55%和8.45%;发生DNA的甲基化和去甲基化位点之比、DNA甲基化多态性均随着干旱胁迫的增强而逐步提高.
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.
Full Text Available From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites--in the promoters of the EDARADD, TOM1L1, and NPTX2 genes--is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. In forensic science, such a model could estimate the age of a person, based on a biological sample alone. Furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age.
An T. Vo
Full Text Available Several of the active compounds in foods, poisons, drugs, and industrial chemicals may, by epigenetic mechanisms, increase or decrease the risk of breast cancers. Enzymes that are involved in DNA methylation and histone modifications have been shown to be altered in several types of breast and other cancers resulting in abnormal patterns of methylation and/or acetylation. Hypermethylation at the CpG islands found in estrogen response element (ERE promoters occurs in conjunction with ligand-bonded alpha subunit estrogen receptor (Erα dimers wherein the ligand ERα dimer complex acts as a transcription factor and binds to the ERE promoter. Ligands could be 17-β-estradiol (E2, phytoestrogens, heterocyclic amines, and many other identified food additives and heavy metals. The dimer recruits DNA methyltransferases which catalyze the transfer of methyl groups from S-adenosyl-L-methionine (SAM to 5′-cytosine on CpG islands. Other enzymes are recruited to the region by ligand-ERα dimers which activate DNA demethylases to act simultaneously to increase gene expression of protooncogenes and growth-promoting genes. Ligand-ERα dimers also recruit histone acetyltransferase to the ERE promoter region. Histone demethylases such as JMJD2B and histone methyltransferases are enzymes which demethylate lysine residues on histones H3 and/or H4. This makes the chromatin accessible for transcription factors and enzymes.
Rivollier, F; Lotersztajn, L; Chaumette, B; Krebs, M-O; Kebir, O
Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post
Pacis, Alain; Nédélec, Yohann; Barreiro, Luis B
The response of host immune cells to microbial stimuli is dependent on robust and coordinated gene expression programs involving the transcription of thousands of genes. The dysregulation of such regulatory programs is likely to significantly contribute to the marked differences in susceptibility to infectious diseases observed among individuals and between human populations. Although the specific factors leading to a dysfunctional immune response to infection remain largely unknown, we are increasingly appreciating the importance of genetic variants in altering the expression levels of immune-related genes, possibly via epigenetic changes. This review describes how recent technological advances have profoundly contributed to our current understanding of the genetic architecture and the epigenetic rules controlling immune responses to infectious agents and how genetic and epigenetic data can be combined to unravel the mechanisms associated with host variation in transcriptional responses to infection.
Slomko, Howard; Heo, Hye J; Einstein, Francine H
Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation.
Johnson, William M.; Wilson-Delfosse, Amy L.; Mieyal, John. J.
Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated. PMID:23201762
Johnson, William M; Wilson-Delfosse, Amy L; Mieyal, John J
Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, and Friedreich's ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.
Crews, David; Gillette, Ross; Miller-Crews, Isaac; Gore, Andrea C.; Skinner, Michael K.
Real life by definition combines heritability (e.g., the legacy of exposures) and experience (e.g. stress during sensitive or ‘critical’ periods), but how to study or even model this interaction has proven difficult. The hoary concept of evaluating traits according to nature vs. nurture continues to persist despite repeated demonstrations that it retards, rather than advances, our understanding of biological processes. Behavioral genetics has proven the obvious, that genes influences behavior and, vice versa, that behavior influences genes. The concept of Genes X Environment (G X E) and its modern variants was viewed as an improvement on nature-nurture but has proven that, except in rare instances, it is not possible to fractionate phenotypes into these constituent elements. The entanglement inherent in terms such as nature-nurture or GXE is a Gordian knot that cannot be dissected or even split. Given that the world today is not what it was less than a century ago, yet the arbitrator (differential survival and reproduction) has stayed constant, de novo principles and practices are needed to better predict what the future holds. Put simply, the transformation that is now occurring within and between individuals as a product of global endocrine disruption is quite independent of what has been regarded as evolution by selection. This new perspective should focus on how epigenetic modifications might revise approaches to understand how the phenotype and, in particular its components, is shaped. In this review we summarize the literature in this developing area, focusing on our research on the fungicide vinclozolin. PMID:25102229
Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Ross, Owen A
Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with Parkinson's disease (PD) pathogenesis. Changes in gene expression are a well-established cause of PD, and epigenetic mechanisms likely play a pivotal role in regulation. Studies in families with PD harboring duplications and triplications of the SNCA gene have demonstrated that gene dosage is associated with increased expression of both SNCA mRNA and protein, and correlates with a fulminant disease course. Furthermore, it is postulated that even subtle changes in SNCA expression caused by common variation is associated with disease risk. Of note, genome-wide association studies have identified over 30 loci associated with PD with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. In health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this, in part, explains why two cells with the same DNA sequence will have different RNA expression profiles. Understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the PD brain. In this review, we discuss epigenetic mechanisms, such as DNA methylation and histone modifications, involved in regulating the expression of genes relevant to PD, RNA-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for PD.
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.
Pinborg, Anja; Loft, Anne; Romundstad, Liv B; Wennerholm, Ulla-Britt; Söderström-Anttila, Viveca; Bergh, Christina; Aittomäki, Kristiina
Epigenetic modification controls gene activity without changes in the DNA sequence. The genome undergoes several phases of epigenetic programming during gametogenesis and early embryo development, coinciding with assisted reproductive technologies (ART) treatments. Imprinting disorders have been associated with ART techniques, but disentangling the influence of the ART procedures per se from the effect of the reproductive disease of the parents is a challenge. Epidemiological human studies have shown altered birthweight profiles in ART compared with spontaneously conceived singletons. Conception with cryopreserved/thawed embryos results in a higher risk of large-for-gestational-age babies, which may be due to epigenetic modification. Further animal studies have shown altered gene expression profiles in offspring conceived by ART related to altered glucose metabolism. It is controversial whether human adolescents conceived by ART have altered lipid and glucose profiles and thereby a higher long-term risk of cardiovascular disease and diabetes. This commentary describes the basic concepts of epigenetics and gives a short overview of the existing literature on the association between imprinting disorders, epigenetic modification and ART. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.
Zannas, A S; Chrousos, G P
Psychosocial stress triggers a set of behavioral, neural, hormonal, and molecular responses that can be a driving force for survival when adaptive and time-limited, but may also contribute to a host of disease states if dysregulated or chronic. The beneficial or detrimental effects of stress are largely mediated by the hypothalamic-pituitary axis, a highly conserved neurohormonal cascade that culminates in systemic secretion of glucocorticoids. Glucocorticoids activate the glucocorticoid receptor, a ubiquitous nuclear receptor that not only causes widespread changes in transcriptional programs, but also induces lasting epigenetic modifications in many target tissues. While the epigenome remains sensitive to stressors throughout life, we propose two key principles that may govern the epigenetics of stress and glucocorticoids along the lifespan: first, the presence of distinct life periods, during which the epigenome shows heightened plasticity to stress exposure, such as in early development and at advanced age; and, second, the potential of stress-induced epigenetic changes to accumulate throughout life both in select chromatin regions and at the genome-wide level. These principles have important clinical and translational implications, and they show striking parallels with the existence of sensitive developmental periods and the cumulative impact of stressful experiences on the development of stress-related phenotypes. We hope that this conceptual mechanistic framework will stimulate fruitful research that aims at unraveling the molecular pathways through which our life stories sculpt genomic function to contribute to complex behavioral and somatic phenotypes.Molecular Psychiatry advance online publication, 14 March 2017; doi:10.1038/mp.2017.35.
Stålberg, P; Westin, G; Thirlwell, C
Neuroendocrine tumour of the small intestine (SI-NET), formerly known as midgut carcinoid tumour, is the most common small intestinal malignancy. The incidence is rising, with recent reports of 0.67 per 100 000 in the USA and 1.12 per 100 000 in Sweden. SI-NETs often present a challenge in terms of diagnosis and treatment, as patients often have widespread disease and are beyond cure by surgery. Somatostatin analogues provide the mainstay of medical treatment to control hormonal excess and increase the time to progression. Despite overall favourable prognosis (5-year overall survival of 65%), there is a need to find markers to identify both patients with worse outcome and new targets for therapy. Loss on chromosome 18 has been reported in 60-90% of SI-NETs, but mutated genes on this chromosome have failed detection. Recently, a putative tumour suppressor role has been suggested for TCEB3C occurring at 18q21 (encoding elongin A3), which may undergo epigenetic repression. CDKN1B has recently been revealed as the only recurrently mutated gene in SI-NETs but, with a frequency as low as 8%, its role as a driver in SI-NET development may be questioned. Integrated genomewide analysis including exome and whole-genome sequencing, gene expression, DNA methylation and copy number analysis has identified three novel molecular subtypes of SI-NET with differing clinical outcome. DNA methylation analysis has demonstrated that SI-NETs have significant epigenetic dysregulation in 70-80% of tumours. In this review, we focus on understanding of the genetic, epigenetic and molecular events that lead to development and progression of SI-NETs.
Pickersgill, Martyn; Niewöhner, Jörg; Müller, Ruth; Martin, Paul; Cunningham-Burley, Sarah
Epigenetics is the study of changes in gene expression caused by mechanisms other than changes in the DNA itself. The field is rapidly growing and being widely promoted, attracting attention in diverse arenas. These include those of the social sciences, where some researchers have been encouraged by the resonance between imaginaries of development within epigenetics and social theory. Yet, sustained attention from science and technology studies (STS) scholars to epigenetics and the praxis it propels has been lacking. In this article, we reflexively consider some of the ways in which epigenetics is being constructed as an area of biomedical novelty and discuss the content and logics underlying the ambivalent promises being made by scientists working in this area. We then reflect on the scope, limits and future of engagements between epigenetics and the social sciences. Our discussion is situated within wider literatures on biomedicine and society, the politics of “interventionist STS,” and on the problems of “caseness” within empirical social science. PMID:24482610
Hepatocellular carcinoma is the main type of primary liver cancer,and also one of the most malignant tumors.At present,the pathogenesis mechanisms of liver cancer are not entirely clear.It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis,caused by the genetic and epigenetic aberrance.In the past,people generally thought that genetic mutation is a key event of tumor pathogenesis,and somatic mutation of tumor suppressor genes is in particular closely associated with oncogenesis.With deeper understanding of tumors in recent years,increasing evidence has shown that epigenetic silencing of those genes,as a result of aberrant hypermethylation of CpG islands in promoters and histone modification,is essential to carcinogenesis and metastasis.The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms,other than changes in the underlying DNA sequence.Specific epigenetic processes include DNA methylation,genome imprinting,chromotin remodeling,histone modification and microRNA regulations.This paper reviews recent epigenetics research progress in the hepatocellular carcinoma study,and tries to depict the relationships between hepatocellular carcinomagenesis and DNA methylation as well as microRNA regulation.
Hepatocellular carcinoma is the main type of primary liver cancer, and also one of the most malignant tumors. At present, the pathogenesis mechanisms of liver cancer are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic aberrance. In the past, people generally thought that genetic mutation is a key event of tumor pathogenesis, and somatic mutation of tumor suppressor genes is in particular closely associated with oncogenesis. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in the underlying DNA sequence. Specific epi-genetic processes include DNA methylation, genome imprinting, chromotin remodeling, histone modi-fication and microRNA regulations. This paper reviews recent epigenetics research progress in the hepatocellular carcinoma study, and tries to depict the relationships between hepatocellular carci-nomagenesis and DNA methylation as well as microRNA regulation.
Epigenetic gene silencing occurs in many important biological processes including differentiation, senescence and imprinting. In most cases, epigenetic silencing is orchestrated by an intricate interplay between DNA methylation, histone modifications and nucleosome remodeling that act in concert to
Lind, Mads Vendelbo
Background: Dysregulation of one-carbon metabolism (OCM) is related to metabolic syndrome (MetS) through various mechanisms including epigenetics. Diet plays a central role in ensuring normal OCM regulation by supplying multiple nutrients. Foods such as whole grains and fish have been proposed...... acid (EPA) and docosahexaenoic acid (DHA) which might also play a role in OCM regulation and epigenetics. Aim: This PhD thesis investigates the role of diet in OCM regulation and the potential association between OCM and MetS. We further investigated whether a dietary intervention with high whole grain......-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH) and Hcy, and diet. Associations between OCM metabolites and MetS features were also investigated. In an 8-week human cross-over intervention study we investigated whether a diet rich in whole grain compared to a diet rich in refined grain could affect OCM metabolites...
Feil, Robert; Fraga, Mario F
Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.
Pinborg, Anja; Loft, Anne; Romundstad, Liv Bente
associated with ART techniques, but disentangling the influence of the ART procedures per se from the effect of the reproductive disease of the parents is a challenge. Epidemiological human studies have shown altered birth weight profiles in ART compared with spontaneously conceived singletons. Conception......Epigenetic modification controls gene activity without changes in the DNA sequence. The genome undergoes several phases of epigenetic programming during gametogenesis and early embryo development coinciding with assisted reproductive technologies (ART) treatments. Imprinting disorders have been...... with cryopreserved/thawed embryos results in a higher risk of large-for-gestational age babies, which may be due to epigenetic modification. Further animal studies have shown altered gene expression profiles in offspring conceived by ART related to altered glucose metabolism. It is controversial whether human...
Full Text Available Chronic heart failure (HF is a leading clinical and public problem posing a higher risk of morbidity and mortality in different populations. HF appears to be in both phenotypic forms: HF with reduced left ventricular ejection fraction (HFrEF and HF with preserved left ventricular ejection fraction (HFpEF. Although both HF phenotypes can be distinguished through clinical features, co-morbidity status, prediction score, and treatment, the clinical outcomes in patients with HFrEF and HFpEF are similar. In this context, investigation of various molecular and cellular mechanisms leading to the development and progression of both HF phenotypes is very important. There is emerging evidence that epigenetic regulation may have a clue in the pathogenesis of HF. This review represents current available evidence regarding the implication of epigenetic modifications in the development of different HF phenotypes and perspectives of epigenetic-based therapies of HF.
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
Toh, Tan Boon; Lim, Jhin Jieh; Chow, Edward Kai-Hua
Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.
Banaudha, Krishna K; Verma, Mukesh
Liver cancer (hepatocellular carcinoma or HCC) is a major cancer worldwide. Research in this field is needed to identify biomarkers that can be used for early detection of the disease as well as new approaches to its treatment. Epigenetic biomarkers provide an opportunity to understand liver cancer etiology and evaluate novel epigenetic inhibitors for treatment. Traditionally, liver cirrhosis, proteomic biomarkers, and the presence of hepatitis viruses have been used for the detection and diagnosis of liver cancer. Promising results from microRNA (miRNA) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers. Some of these epigenetic biomarkers may be useful in risk assessment and for screening populations to identify who is likely to develop cancer. Challenges and opportunities in the field are discussed in this chapter.
Yan Jia; Mingzhou Guo
Epigenetic changes frequently occur in human colorectal cancer.Genomic global hypomethylation,gene promoter region hypermethylation,histone modifications,and alteration of miRNA patterns are major epigenetic changes in colorectal cancer.Loss of imprinting (LOI) is associated with colorectal neoplasia.Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation.HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment.Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer.This review is mainly focused on DNA methylation,histone modification,and microRNA changes in colorectal cancer.
Meulenbelt, Ingrid M; Bhutani, Nidhi; den Hollander, Wouter; Gay, Steffen; Oppermann, Udo; Reynard, Louise N; Skelton, Andrew J; Young, David A; Beier, Frank; Loughlin, John
Osteoarthritis (OA) is a major clinical problem across the world, in part due to the lack of disease-modifying drugs resulting, to a significant degree, from our incomplete understanding of the underlying molecular mechanisms of the disease. Emerging evidence points to a role of epigenetics in the pathogenesis of OA, but research in this area is still in its early stages. In order to summarize current knowledge and to facilitate the potential coordination of future research activities, the first international workshop on the epigenetics of OA was held in Amsterdam in October 2015. Recent findings on DNA methylation and hydroxymethylation, histone modifications, noncoding RNAs, and other epigenetic mechanisms were presented and discussed. The workshop demonstrated the advantage of bringing together those working in this nascent field and highlights from the event are summarized in this report in the form of summaries from invited speakers and organizers.
Epigenetic programming is likely to be an important mechanism underlying the lasting influence of the developmental environment on lifelong health, a concept known as the Developmental Origins of Health and Disease (DOHaD). DNA methylation, posttranslational histone protei n modi...
Epigenetic programming is likely to be an important mechanism underlying the lasting influence of the developmental environment on lifelong health, a concept known as the Developmental Origins of Health and Disease (DOHaD). DNA methylation, posttranslational histone protei n modi...
Flueck, Christian; Baker, David A
Blood-stage malaria parasites evade the immune system by switching the protein exposed at the surface of the infected erythrocyte. A small proportion of these parasites commits to sexual development to mediate mosquito transmission. Two studies in this issue (Brancucci et al., 2014; Coleman et al., 2014) shed light on shared epigenetic machinery underlying both of these events.
Amy Vaughn Whipple
Full Text Available The study of epigenomic variation at the landscape-level in plants may add important insight to studies of adaptive variation. A major goal of landscape genomic studies is to identify genomic regions contributing to adaptive variation across the landscape. Heritable variation in epigenetic marks, resulting in transgenerational plasticity, can influence fitness-related traits. Epigenetic marks are influenced by the genome, the environment, and their interaction, and can be inherited independently of the genome. Thus, epigenomic variation likely influences the heritability of many adaptive traits, but the extent of this influence remains largely unknown. Here we summarize the relevance of epigenetic inheritance to ecological and evolutionary processes, and review the literature on landscape-level patterns of epigenetic variation. Landscape-level patterns of epigenomic variation in plants generally show greater levels of isolation by distance and isolation by environment then is found for the genome, but the causes of these patterns are not yet clear. Linkage between the environment and epigenomic variation has been clearly shown within a single generation, but demonstrating transgenerational inheritance requires more complex breeding and/or experimental designs. Transgenerational epigenetic variation may alter the interpretation of landscape genomic studies that rely upon phenotypic analyses, but should have less influence on landscape genomic approaches that rely upon outlier analyses or genome-environment associations. We suggest that multi-generation common garden experiments conducted across multiple environments will allow researchers to understand which parts of the epigenome are inherited, as well as to parse out the relative contribution of heritable epigenetic variation to the phenotype.
Banister, Carolyn E
The study of epigenetics has experienced exponential growth in the past 15 years and continues to be a major focus of study across biological disciplines. A new reference text Epigenetics: A Reference Manual, published by Caister Academic Press and edited by Jeffrey M. Craig and Nicholas C. Wong (Developmental Epigenetics Group, Murdoch Children's Research Institute, Victoria, Australia), presents a current and comprehensive look into the many facets of epigenetics research. The information t...
Donkin, Ida; Barrès, Romain; Pinborg, Anja
The epigenome is sensitive to environmental changes and can sustainably alter gene expression, notably during embryonic development. New research indicates that epigenetic factors are heritable, which is why paternal lifestyle may affect fetal development and risk of disease. Children conceived...... by assisted reproduction technology (ART) have an increased risk of peri- and postnatal complications, and as specific ART protocols associate with specific risk profiles, the procedures themselves may cause epigenetic changes contributing to the altered outcomes of the 5,000 Danish children annually...
Li-Ming; Yu; Yong; Xu
Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this minireview, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs.
In-Seon CHOI; Tsung-Teh WU
Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.
Houde, Andrée-Anne; Hivert, Marie-France; Bouchard, Luigi
Epigenetics generates a considerable interest in the field of research on complex traits, including obesity and diabetes. Recently, we reported a number of epipolymorphisms in the placental leptin and adiponectin genes associated with maternal hyperglycemia during pregnancy. Our results suggest that DNA methylation could partly explain the link between early exposure to a detrimental fetal environment and an increased risk to develop obesity and diabetes later in life. This brief report discusses the potential importance of adipokine epigenetic changes in fetal metabolic programming. Additionally, preliminary data showing similarities between methylation variations of different tissues and cell types will be presented along with the challenges and future perspectives of this emerging field of research.
Zybura-Broda, Katarzyna; Amborska, Renata; Ambrozek-Latecka, Magdalena; Wilemska, Joanna; Bogusz, Agnieszka; Bucko, Joanna; Konopka, Anna; Grajkowska, Wieslawa; Roszkowski, Marcin; Marchel, Andrzej; Rysz, Andrzej; Koperski, Lukasz; Wilczynski, Grzegorz M.; Kaczmarek, Leszek; Rylski, Marcin
Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms–DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45β to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the
Zybura-Broda, Katarzyna; Amborska, Renata; Ambrozek-Latecka, Magdalena; Wilemska, Joanna; Bogusz, Agnieszka; Bucko, Joanna; Konopka, Anna; Grajkowska, Wieslawa; Roszkowski, Marcin; Marchel, Andrzej; Rysz, Andrzej; Koperski, Lukasz; Wilczynski, Grzegorz M; Kaczmarek, Leszek; Rylski, Marcin
Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms-DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45β to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the
Vaniushin, B F
sensitive to DNA methylation. It seems likely that plants, similarly to microorganisms and some lower eukaryotes, have restriction--modification (R--M) system. Discovery of the essential role of DNA methylation in regulation of genetic processes served as a principle basis and materialization of epigenetics and epigenomics.
Samson, Andrea C.; Phillips, Jennifer M.; Parker, Karen J.; Shah, Shweta; Gross, James J.; Hardan, Antonio Y.
The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child…
Hatzenbuehler, Mark L.; Nolen-Hoeksema, Susan
Background Emotion regulation deficits have been consistently linked to psychopathology in cross-sectional studies. However, the direction of the relationship between emotion regulation and psychopathology is unclear. This study examined the longitudinal and reciprocal relationships between emotion regulation deficits and psychopathology in adolescents. Methods Emotion dysregulation and symptomatology (depression, anxiety, aggressive behavior, and eating pathology) were assessed in a large, diverse sample of adolescents (N = 1,065) at two time points separated by seven months. Structural equation modeling was used to examine the longitudinal and reciprocal relationships between emotion dysregulation and symptoms of psychopathology. Results The three distinct emotion processes examined here (emotional understanding, dysregulated expression of sadness and anger, and ruminative responses to distress) formed a unitary latent emotion dysregulation factor. Emotion dysregulation predicted increases in anxiety symptoms, aggressive behavior, and eating pathology after controlling for baseline symptoms but did not predict depressive symptoms. In contrast, none of the four types of psychopathology predicted increases in emotion dysregulation after controlling for baseline emotion dysregulation. Conclusions Emotion dysregulation appears to be an important transdiagnostic factor that increases risk for a wide range of psychopathology outcomes in adolescence. These results suggest targets for preventive interventions during this developmental period of risk. PMID:21718967
In many biological processes, the regulation of gene expression involves epigenetic mechanisms. An altered pattern of epigenetic modification is central to many animal diseases. Using animal disease models, we have studied one of the major epigenetic components: DNA methylation. We characterized the...
Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine; Whiteside, Charisse; Coleman, Paul D.; Rogers, Joseph
Epigenetic modifications help orchestrate sweeping developmental, aging, and disease-causing changes in phenotype by altering transcriptional activity in multiple genes spanning multiple biologic pathways. Although previous epigenetic research has focused primarily on dividing cells, particularly in cancer, recent studies have shown rapid, dynamic, and persistent epigenetic modifications in neurons that have significant neuroendocrine, neurophysiologic, and neurodegenerative consequences. Her...
through multiple epigenetic mechanisms. This paper reviews the new developments in using twins to study disease-related epigenetic alterations, links them to lifetime environmental exposure with a focus on the discordant twin design and proposes novel data-analytical approaches with the aim of promoting...... a more efficient use of twins in epigenetic studies of complex human diseases....
Omar ede Faria Jr.
Full Text Available Multiple Sclerosis (MS is a chronic inflammatory disease characterized by central nervous system (CNS demyelination and axonal degeneration. Although the cause of MS is still unknown, it is widely accepted that novel drug targets need to focus on both decreasing inflammation and promoting CNS repair. In MS and experimental autoimmune encephalomyelitis (EAE non-coding small microRNAs (miRNAs are dysregulated in the immune and central nervous systems. Since individual miRNAs are able to downregulate multiple targeted mRNA transcripts, even minor changes in miRNA expression may lead to significant alterations in post-transcriptional gene expression. Herein, we review miRNA signatures reported in CNS tissue and immune cells of MS patients and consider how altered miRNA expression may influence MS pathology.
Sams, Richard; LaBrie, D Walter; Norris, Jacob; Schauer, Judy; Frantz, Earl
Concussions are the most frequent battle injury sustained in Afghanistan. The Concussion Restoration Care Center provides multidisciplinary care to concussed service members in theater. The Concussion Restoration Care Center has managed over 500 concussions, the majority being from improvised explosive device (IED) blasts. Syncope following a concussion without a loss of consciousness is rarely reported in the literature. The pathophysiology of concussion from a blast injury may be distinct from a concussion secondary to blunt trauma. Two cases of syncope following concussions with an alteration of consciousness are presented, and a mechanism of action is proposed. Post-IED blast concussive symptom frequency at initial presentation on a cohort of patients is reported, with 1.3% of patients experiencing postconcussive syncope. Syncope following an IED blast may be related to centrally mediated autonomic dysregulation at the brain stem level. Syncope should be added to the list of possible symptoms that occur following concussions, in particular concussions following a blast injury.
Feber, Janusz; Ruzicka, Marcel; Geier, Pavel; Litwin, Mieczyslaw
Historically, primary hypertension (HTN) has been prevalent typically in adults. Recent data however, suggests an increasing number of children diagnosed with primary HTN, mainly in the setting of obesity. One of the factors considered in the etiology of HTN is the autonomous nervous system, namely its dysregulation. In the past, the sympathetic nervous system (SNS) was regarded as a system engaged mostly in buffering major acute changes in blood pressure (BP), in response to physical and emotional stressors. Recent evidence suggests that the SNS plays a much broader role in the regulation of BP, including the development and maintenance of sustained HTN by a chronically elevated central sympathetic tone in adults and children with central/visceral obesity. Consequently, attempts have been made to reduce the SNS hyperactivity, in order to intervene early in the course of the disease and prevent HTN-related complications later in life.
Knopik, Valerie S; Maccani, Matthew A; Francazio, Sarah; McGeary, John E
The period of in utero development is one of the most critical windows during which adverse intrauterine conditions and exposures can influence the growth and development of the fetus as well as the child's future postnatal health and behavior. Maternal cigarette smoking during pregnancy remains a relatively common but nonetheless hazardous in utero exposure. Previous studies have associated prenatal smoke exposure with reduced birth weight, poor developmental and psychological outcomes, and increased risk for diseases and behavioral disorders later in life. Researchers are now learning that many of the mechanisms whereby maternal smoke exposure may affect key pathways crucial for proper fetal growth and development are epigenetic in nature. Maternal cigarette smoking during pregnancy has been associated with altered DNA methylation and dysregulated expression of microRNA, but a deeper understanding of the epigenetics of maternal cigarette smoking during pregnancy as well as how these epigenetic changes may affect later health and behavior remain to be elucidated. This article seeks to explore many of the previously described epigenetic alterations associated with maternal cigarette smoking during pregnancy and assess how such changes may have consequences for both fetal growth and development, as well as later child health, behavior, and well-being. We also outline future directions for this new and exciting field of research.
Multhaup, Michael L.; Seldin, Marcus; Jaffe, Andrew E.; Lei, Xia; Kirchner, Henriette; Mondal, Prosenjit; Li, Yuanyuan; Rodriguez, Varenka; Drong, Alexander; Hussain, Mehboob; Lindgren, Cecilia; McCarthy, Mark; Näslund, Erik; Zierath, Juleen R.; Wong, G. William; Feinberg, Andrew P.
SUMMARY Using a functional approach to investigate the epigenetics of Type 2 Diabetes (T2D), we combine three lines of evidence – diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence – to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change is conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk. PMID:25565211
Full Text Available Pulmonary arterial hypertension (PAH is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date.
Bräutigam, Katharina; Vining, Kelly J; Lafon-Placette, Clément; Fossdal, Carl G; Mirouze, Marie; Marcos, José Gutiérrez; Fluch, Silvia; Fraga, Mario Fernández; Guevara, M Ángeles; Abarca, Dolores; Johnsen, Øystein; Maury, Stéphane; Strauss, Steven H; Campbell, Malcolm M; Rohde, Antje; Díaz-Sala, Carmen; Cervera, María-Teresa
Epigenetic variation is likely to contribute to the phenotypic plasticity and adaptative capacity of plant species, and may be especially important for long-lived organisms with complex life cycles, including forest trees. Diverse environmental stresses and hybridization/polyploidization events can create reversible heritable epigenetic marks that can be transmitted to subsequent generations as a form of molecular “memory”. Epigenetic changes might also contribute to the ability of plants to colonize or persist in variable environments. In this review, we provide an overview of recent data on epigenetic mechanisms involved in developmental processes and responses to environmental cues in plant, with a focus on forest tree species. We consider the possible role of forest tree epigenetics as a new source of adaptive traits in plant breeding, biotechnology, and ecosystem conservation under rapid climate change. PMID:23467802
Walsh, Louise; Gallagher, William M; O'Connor, Darran P; Ní Chonghaile, Tríona
Breast cancer is the most common cancer in women and great advancements have been made for individualised patient treatment. Through understanding the underlying altered biology in the different subtypes of breast cancer, targeted therapeutics have been developed. Unfortunately, resistance to targeted therapy, intrinsic or acquired, is a recurring theme in cancer treatment. Epigenetic-mediated resistance to targeted therapy has been identified across different types of cancer. In addition, tumorigenesis has also been linked to altered expression of epigenetic modifiers. Due to the reversible nature of epigenetic modifications, epigenetic proteins are appealing as therapeutic targets in both the primary and relapsed/resistant setting. In this review, we will discuss the current state of targetable epigenetic histone modifications and their diagnostic and therapeutic implications in breast cancer.
Rice, William R; Friberg, Urban; Gavrilets, Sergey
We recently synthesized and reinterpreted published studies to advance an epigenetic model for the development of homosexuality (HS). The model is based on epigenetic marks laid down in response to the XX vs. XY karyotype in embryonic stem cells. These marks boost sensitivity to testosterone in XY fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our model predicts that a subset of these canalizing epigenetic marks stochastically carry over across generations and lead to mosaicism for sexual development in opposite-sex offspring--the homosexual phenotype being one such outcome. Here, we begin by outlining why HS has been under-appreciated as a commonplace phenomenon in nature, and how this trend is currently being reversed in the field of neurobiology. We next briefly describe our epigenetic model of HS, develop a set of predictions, and describe how epigenetic profiles of human stem cells can provide for a strong test of the model.
van Dijk, Susan J; Tellam, Ross L; Morrison, Janna L; Muhlhausler, Beverly S; Molloy, Peter L
.... This has led to growing interest in understanding the potential role of epigenetics as a mediator of gene-environment interactions underlying the development of obesity and its associated comorbiditi...
T. Muka (Taulant); F. Koromani (Fjorda); E. Portilla (Eliana); A. O'Connor (Annalouise); W.M. Bramer (Wichor); J. Troup; R. Chowdhury (Rajiv); A. Dehghan (Abbas); O.H. Franco (Oscar)
textabstractBackground Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in processes underlying cardiovascular disease (CVD), including atherosclerosis, inflammation, hypertension and diabetes. Methods Eleven databases were
Prenatal and early postnatal environment can persistently alter one's risk of obesity. Environmental effects on hypothalamic developmental epigenetics constitute a likely mechanism underlying such 'developmental programming' of energy balance regulation. To advance our understanding of these process...
Ozone (03) is a criteria air pollutant that is associated with numerous adverse health effects, including altered respiratory immune responses. Despite its deleterious health effects, possible epigenetic mechanisms underlying 03-induced health effects remain understudied. MicroRN...
Foust, C.M.; Preite, V.; Schrey, Aaron W.; Alvarez, M.; Robertson, M.H.; Verhoeven, K.J.F.; Richards, C.L.
While traits and trait plasticity are partly genetically based, investigating epigenetic mechanisms may provide more nuanced understanding of the mechanisms underlying response to environment. Using AFLP and methylation-sensitive AFLP, we tested the hypothesis that differentiation to habitats along
Preeclampsia (PE) affects 8-10% of women in the US and long-term consequences include subsequent development of maternal hypertension and hypertension in offspring. As methylation patterns are established during fetal life, we focused on epigenetic alterations in DNA methylation as a plausible expla...
The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.
Godfrey, Keith M; Costello, Paula; Lillycrop, Karen
It is now widely recognised that the environment in early life can have important effects on human growth and development, including the “programming” of far reaching effects on the risk of developing common metabolic and other non-communicable diseases in later life. We have shown that greater childhood adiposity is associated with higher maternal adiposity, low maternal vitamin D status, excessive gestational weight gain, and short duration of breastfeeding; maternal dietary patterns in pregnancy and vitamin D status have been linked with childhood bone mineral content and muscle function. Human studies have identified fetal liver blood flow adaptations and epigenetic changes as potential mechanisms that could link maternal influences with offspring body composition. In experimental studies there is now substantial evidence that the environment during early life induces altered phenotypes through epigenetic mechanisms. Epigenetic processes such as DNA methylation, covalent modifications of histones and non-coding RNAs can induce changes in gene expression without a change in DNA base sequence. Such processes are involved in cell differentiation and genomic imprinting, as well as the phenomenon of developmental plasticity in response to environmental influences. Elucidation of such epigenetic processes may enable early intervention strategies to improve early development and growth. PMID:27088334
Champagne, Frances A.
Advances in understanding of the dynamic molecular interplay between DNA and its surrounding proteins suggest that epigenetic mechanisms are a critical link between early life experiences (e.g., prenatal stress, parent-offspring interactions) and long-term changes in brain and behavior. Although much of this evidence comes from animal studies,…
Beck, Hans Christian
-based proteomics techniques to histone biology has gained new insight into the function of the nucleosome: Novel posttranslational modifications have been discovered at the lateral surface of the nucleosome. These modifications regulate histone-DNA interactions, adding a new dimension to the epigenetic regulation...
Grafodatskaya, Daria; Chung, Brian; Szatmari, Peter; Weksberg, Rosanna
Objective: Current research suggests that the causes of autism spectrum disorders (ASD) are multifactorial and include both genetic and environmental factors. Several lines of evidence suggest that epigenetics also plays an important role in ASD etiology and that it might, in fact, integrate genetic and environmental influences to dysregulate…
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.
Champagne, Frances A.
Advances in understanding of the dynamic molecular interplay between DNA and its surrounding proteins suggest that epigenetic mechanisms are a critical link between early life experiences (e.g., prenatal stress, parent-offspring interactions) and long-term changes in brain and behavior. Although much of this evidence comes from animal studies,…
Grafodatskaya, Daria; Chung, Brian; Szatmari, Peter; Weksberg, Rosanna
Objective: Current research suggests that the causes of autism spectrum disorders (ASD) are multifactorial and include both genetic and environmental factors. Several lines of evidence suggest that epigenetics also plays an important role in ASD etiology and that it might, in fact, integrate genetic and environmental influences to dysregulate…
Tan, Qihua; Christiansen, Lene; von Bornemann Hjelmborg, Jacob; Christensen, Kaare
Since the final decades of the last century, twin studies have made a remarkable contribution to the genetics of human complex traits and diseases. With the recent rapid development in modern biotechnology of high-throughput genetic and genomic analyses, twin modelling is expanding from analysis of diseases to molecular phenotypes in functional genomics especially in epigenetics, a thriving field of research that concerns the environmental regulation of gene expression through DNA methylation, histone modification, microRNA and long non-coding RNA expression, etc. The application of the twin method to molecular phenotypes offers new opportunities to study the genetic (nature) and environmental (nurture) contributions to epigenetic regulation of gene activity during developmental, ageing and disease processes. Besides the classical twin model, the case co-twin design using identical twins discordant for a trait or disease is becoming a popular and powerful design for epigenome-wide association study in linking environmental exposure to differential epigenetic regulation and to disease status while controlling for individual genetic make-up. It can be expected that novel uses of twin methods in epigenetic studies are going to help with efficiently unravelling the genetic and environmental basis of epigenomics in human complex diseases.
Rajeevkumar, Sarma; Anunanthini, Pushpanathan; Sathishkumar, Ramalingam
Epigenetic silencing is a natural phenomenon in which the expression of genes is regulated through modifications of DNA, RNA, or histone proteins. It is a mechanism for defending host genomes against the effects of transposable elements and viral infection, and acts as a modulator of expression of duplicated gene family members and as a silencer of transgenes. A major breakthrough in understanding the mechanism of epigenetic silencing was the discovery of silencing in transgenic tobacco plants due to the interaction between two homologous promoters. The molecular mechanism of epigenetic mechanism is highly complicated and it is not completely understood yet. Two different molecular routes have been proposed for this, that is, transcriptional gene silencing, which is associated with heavy methylation of promoter regions and blocks the transcription of transgenes, and post-transcriptional gene silencing (PTGS), the basic mechanism is degradation of the cytosolic mRNA of transgenes or endogenous genes. Undesired transgene silencing is of major concern in the transgenic technologies used in crop improvement. A complete understanding of this phenomenon will be very useful for transgenic applications, where silencing of specific genes is required. The current status of epigenetic silencing in transgenic technology is discussed and summarized in this mini-review. PMID:26442010
Full Text Available Stable molecular changes during cell division without change the sequence of DNA molecules is known as epigenetic. Molecular mechanisms involved in this process, including histone modifications, methylation of DNA, protein complex and RNA antisense. Cancer genome changes happen through a combination of DNA hypermethylation, long-term epigenetic silencing with heterozygosis loss and genomic regions loss. Different combinations of N-terminal changes cooperation with histone variants with have a specific role in gene regulation have led to load a setting histone that determine transcription potential of a particular gene or genomic regions. DNA methylation analysis in genome region using methylation-specific digital karyotyping of normal breast tissue detect gene expression patterns and DNA specific methylation can be found in breast carcinoma too. More than 100 genes in breast tumors or cell lines of breast cancer are reported hypermethylated. Important of DNA methylation on cancer has been concentrated CpG islands Hypermethylation. The most of the techniques are able to identify hypermethylated areas. Recent studies have showed the role of epigenetic silencing in the pathogenesis of breast cancer in which tumor suppressor genes have been changed by acetylation and DNA deacetylation. Histone deacetylase inhibitors have different roles in cancer cells and could show the ways of new treatment for breast cancer. In this review, various aspects of breast cancer epigenetics and its applications in diagnosis, prediction and treatment are described.
Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine; Whiteside, Charisse; Coleman, Paul D.; Rogers, Joseph
Epigenetic modifications help orchestrate sweeping developmental, aging, and disease-causing changes in phenotype by altering transcriptional activity in multiple genes spanning multiple biologic pathways. Although previous epigenetic research has focused primarily on dividing cells, particularly in cancer, recent studies have shown rapid, dynamic, and persistent epigenetic modifications in neurons that have significant neuroendocrine, neurophysiologic, and neurodegenerative consequences. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and Alzheimer’s disease (AD). Because of their reach across the genome, epigenetic mechanisms may provide a unique integrative framework for the pathologic diversity and complexity of AD. PMID:21482442
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
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.
Full Text Available Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development.
Maumus, Florian; Rabinowicz, Pablo; Bowler, Chris; Rivarola, Maximo
Epigenetics include DNA methylation, the modification of histone tails that affect chromatin states, and small RNAs that are involved in the setting and maintenance of chromatin modifications. Marine stramenopiles (MAS), which are a diverse assemblage of algae that acquired photosynthesis from secondary endosymbiosis, include single-celled organisms such as diatoms as well as multicellular forms such as brown algae. The recent publication of two diatom genomes that diverged ~90 million years ago (mya), as well as the one of a brown algae that diverged from diatoms ~250 Mya, provide a great system of related, yet diverged set of organisms to compare epigenetic marks and their relationships. For example, putative DNA methyltransferase homologues were found in diatoms while none could be identified in the brown algal genome. On the other hand, no canonical DICER-like protein was found in diatoms in contrast to what is observed in brown algae. A key interest relies in understanding the adaptive nature of epigenetics and its inheritability. In contrast to yeast that lack DNA methylation, homogeneous cultures of diatoms constitute an attractive system to study epigenetic changes in response to environmental conditions such as nutrient-rich to nutrient-poor transitions which is especially relevant because of their ecological importance. P. tricornutum is also of outstanding interest because it is observed as three different morphotypes and thus constitutes a simple and promising model for the study of the epigenetic phenomena that accompany cellular differentiation. In this review we focus on the insights obtained from MAS comparative genomics and epigenomic analyses.
Nestler, Eric J
Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
Full Text Available For several decades, we have known that epigenetic regulation is disrupted in cancer. Recently, an increasing body of data suggests epigenetics might be an intersection of current cancer research trends: next generation sequencing, immunology, metabolomics, and cell aging. The new emphasis on epigenetics is also related to the increasing production of drugs capable of interfering with epigenetic mechanisms and able to trigger clinical responses in even advanced phase patients. In this review, we will use myeloid malignancies as proof of concept examples of how epigenetic mechanisms can trigger or promote oncogenesis. We will also show how epigenetic mechanisms are related to genetic aberrations, and how they affect other systems, like immune response. Finally, we will show how we can try to influence the fate of cancer cells with epigenetic therapy.
Becker, Claude; Weigel, Detlef
Recent studies have revealed that epigenetic variation in plant populations exceeds genetic diversity and that it is influenced by the environment. Nevertheless, epigenetic differences are not entirely independent of shared ancestry. Epigenetic modifications have gained increasing attention, because one can now study their patterns across the entire genome and in many different individuals. Not only do epigenetic phenomena modulate the activity of the genome in response to environmental stimuli, but they also constitute a potential source of natural variation. Understanding the emergence and heritability of epigenetic variants is critical for understanding how they might become subject to natural selection and thus affect genetic diversity. Here we review progress in characterizing natural epigenetic variants in model and nonmodel plant species and how this work is helping to delineate the role of epigenetic changes in evolution.
Waggoner, Miranda R; Uller, Tobias
The epigenetic "revolution" in science cuts across many disciplines, and it is now one of the fastest growing research areas in biology. Increasingly, claims are made that epigenetics research represents a move away from the genetic determinism that has been prominent both in biological research and in understandings of the impact of biology on society. We discuss to what extent an epigenetic framework actually supports these claims. We show that, in contrast to the received view, epigenetics research is often couched in language as deterministic as genetics research in both science and the popular press. We engage the rapidly emerging conversation about the impact of epigenetics on public discourse and scientific practice, and we contend that the notion of epigenetic determinism - or the belief that epigenetic mechanisms determine the expression of human traits and behaviors - matters for understandings of the influence of biology and society on population health.
Nagy, Corina; Turecki, Gustavo
Much controversy surrounds the idea of transgenerational epigenetics. Recent papers argue that epigenetic marks acquired through experience are passed to offspring, but as in much of the field of epigenetics, there is lack of precision in the definitions and perhaps too much eagerness to translate animal research to humans. Here, we review operational definitions of transgenerational inheritance and the processes of epigenetic programing during early development. Subsequently, based on this background, we critically examine some recent findings of studies investigating transgenerational inheritance. Finally, we discuss possible mechanisms that may explain transgenerational inheritance, including transmission of an epigenetic blueprint, which may predispose offspring to specific epigenetic patterning. Taken together, we conclude that presently, the evidence suggesting that acquired epigenetic marks are passed to the subsequent generation remains limited.
Hong, Xiumei; Wang, Xiaobin
This review aims to highlight the latest advance on epigenetics in the development of food allergy (FA) and to offer future perspectives. FA, a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food, has emerged as a major clinical and public health problem worldwide in light of its increasing prevalence, potential fatality, and significant medical and economic impact. Current evidence supports that epigenetic mechanisms are involved in immune regulation and that the epigenome may represent a key "missing piece" of the etiological puzzle for FA. There are a growing number of population-based epigenetic studies on allergy-related phenotypes, mostly focused on DNA methylation. Previous studies mostly applied candidate-gene approaches and have demonstrated that epigenetic marks are associated with multiple allergic diseases and/or with early-life exposures relevant to allergy development (such as early-life smoking exposure, air pollution, farming environment, and dietary fat). Rapid technological advancements have made unbiased genome-wide DNA methylation studies highly feasible, although there are substantial challenge in study design, data analyses, and interpretation of findings. In conclusion, epigenetics represents both an important knowledge gap and a promising research area for FA. Due to the early onset of FA, epigenetic studies of FA in prospective birth cohorts have the potential to better understand gene-environment interactions and underlying biological mechanisms in FA during critical developmental windows (preconception, in utero, and early childhood) and may lead to new paradigms in the diagnosis, prevention, and management of FA and provide novel targets for future drug discovery and therapies for FA.
Groszmann, Michael; Greaves, Ian K; Fujimoto, Ryo; Peacock, W James; Dennis, Elizabeth S
Hybrid vigour, or heterosis, refers to the increased yield and biomass of hybrid offspring relative to the parents. Although this has been exploited in plants for agriculture and horticulture, the molecular and cellular mechanisms underlying hybrid vigour are largely unknown. Genetic analyses show that there are a large number of quantitative trait loci (QTLs) that contribute to the heterotic phenotype, indicating that it is a complex phenomenon. Gene expression in hybrids is regulated by the interactions of the two parental epigenetic systems and the underlying genomes. Increasing understanding of the interplay of small RNA (sRNA) molecules, DNA methylation, and histone marks provides new opportunities to define the basis of hybrid vigour and to understand why F1 heterosis is not passed on to subsequent generations. We discuss recent findings that suggest the existence of several pathways that alter DNA methylation patterns, which may lead to transcriptional changes resulting in the heterotic phenotype.
Nomura, Yoko; John, Rosalind M; Janssen, Anna Bugge; Davey, Charles; Finik, Jackie; Buthmann, Jessica; Glover, Vivette; Lambertini, Luca
Preeclampsia is known to be a leading cause of mortality and morbidity among mothers and their infants. Approximately 3-8% of all pregnancies in the US are complicated by preeclampsia and another 5-7% by hypertensive symptoms. However, less is known about its long-term influence on infant neurobehavioral development. The current review attempts to demonstrate new evidence for imprinting gene dysregulation caused by hypertension, which may explain the link between maternal preeclampsia and neurocognitive dysregulation in offspring. Pub Med and Web of Science databases were searched using the terms "preeclampsia," "gestational hypertension," "imprinting genes," "imprinting dysregulation," and "epigenetic modification," in order to review the evidence demonstrating associations between preeclampsia and suboptimal child neurodevelopment, and suggest dysregulation of placental genomic imprinting as a potential underlying mechanism. The high mortality and morbidity among mothers and fetuses due to preeclampsia is well known, but there is little research on the long-term biological consequences of preeclampsia and resulting hypoxia on the fetal/child neurodevelopment. In the past decade, accumulating evidence from studies that transcend disciplinary boundaries have begun to show that imprinted genes expressed in the placenta might hold clues for a link between preeclampsia and impaired cognitive neurodevelopment. A sudden onset of maternal hypertension detected by the placenta may result in misguided biological programming of the fetus via changes in the epigenome, resulting in suboptimal infant development. Furthering our understanding of the molecular and cellular mechanisms through which neurodevelopmental trajectories of the fetus/infant are affected by preeclampsia and hypertension will represent an important first step toward preventing adverse neurodevelopment in infants.
Keith A. Maggert
Full Text Available At its broadest sense, to say that a phenotype is epigenetic suggests that it occurs without changes in DNA sequence, yet is heritable through cell division and occasionally from one organismal generation to the next. Since gene regulatory changes are oftentimes in response to environmental stimuli and may be retained in descendent cells, there is a growing expectation that one's experiences may have consequence for subsequent generations and thus impact evolution by decoupling a selectable phenotype from its underlying heritable genotype. But the risk of this overbroad use of “epigenetic” is a conflation of genuine cases of heritable non-sequence genetic information with trivial modes of gene regulation. A look at the term “epigenetic” and some problems with its increasing prevalence argues for a more reserved and precise set of defining characteristics. Additionally, questions arising about how we define the “sequence independence” aspect of epigenetic inheritance suggest a form of genome evolution resulting from induced polymorphisms at repeated loci (e.g., the rDNA or heterochromatin.
Wallack, Lawrence; Thornburg, Kent
The Developmental Origins of Health and Disease and the related science of epigenetics redefines the meaning of what constitutes upstream approaches to significant social and public health problems. An increasingly frequent concept being expressed is "When it comes to your health, your zip code may be more important than your genetic code". Epigenetics explains how the environment-our zip code-literally gets under our skin, creates biological changes that increase our vulnerability for disease, and even children's prospects for social success, over their life course and into future generations. This science requires us to rethink where disease comes from and the best way to promote health. It identifies the most fundamental social equity issue in our society: that initial social and biological disadvantage, established even prior to birth, and linked to the social experience of prior generations, is made worse by adverse environments throughout the life course. But at the same time, it provides hope because it tells us that a concerted focus on using public policy to improve our social, physical, and economic environments can ultimately change our biology and the trajectory of health and social success into future generations.
Sedighi, Mohammad; Sengupta, Anirvan M.
The role of post-translational modification of histones in eukaryotic gene regulation is well recognized. Epigenetic silencing of genes via heritable chromatin modifications plays a major role in cell fate specification in higher organisms. We formulate a coarse-grained model of chromatin silencing in yeast and study the conditions under which the system becomes bistable, allowing for different epigenetic states. We also study the dynamics of the boundary between the two locally stable states of chromatin: silenced and unsilenced. The model could be of use in guiding the discussion on chromatin silencing in general. In the context of silencing in budding yeast, it helps us understand the phenotype of various mutants, some of which may be non-trivial to see without the help of a mathematical model. One such example is a mutation that reduces the rate of background acetylation of particular histone side chains that competes with the deacetylation by Sir2p. The resulting negative feedback due to a Sir protein depletion effect gives rise to interesting counter-intuitive consequences. Our mathematical analysis brings forth the different dynamical behaviors possible within the same molecular model and guides the formulation of more refined hypotheses that could be addressed experimentally.
Bruce, Kimberley D; Cagampang, Felino R
The metabolic syndrome (MetS) represents a cluster of cardiometabolic risk factors, including central obesity, insulin resistance, glucose intolerance, dyslipidemia, hypertension, hyperinsulinemia and microalbuminuria, and more recently, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS) and atherosclerosis. Although the concept of the MetS is subject to debate due to lack of a unifying underlying mechanism, the prevalence of a metabolic syndrome phenotype is rapidly increasing worldwide. Moreover, it is increasingly prevalent in children and adolescents of obese mothers. Evidence from both epidemiological and experimental animal studies now demonstrates that MetS onset is increasingly likely following exposure to suboptimal nutrition during critical periods of development, as observed in maternal obesity. Thus, the developmental priming of the MetS provides a common origin for this multifactorial disorder. Consequently, the mechanisms leading to this developmental priming have recently been the subject of intensive investigation. This review discusses recent data regarding the epigenetic modifications resulting from nutrition during early development that mediate persistent changes in the expression of key metabolic genes and contribute toward an adult metabolic syndrome phenotype. In addition, this review considers the role of the endogenous molecular circadian clock system, which has the potential to act at the interface between nutrient sensing and epigenetic processing. A continued and greater understanding of these mechanisms will eventually aid in the identification of individuals at high risk of cardiovascular disease (CVD) and type 2 diabetes, and help develop therapeutic interventions, in accordance with current global government strategy.
McEwen Kirsten R
types of gene regulation, imprinting and developmental, our results suggest that different histone modifications associate with these distinct processes. This form of analysis is therefore a useful tool to elucidate the complex epigenetic code associated with genome function and to determine the underlying features conferring epigenetic states.
Full Text Available Ion signaling and transduction networks are central to fungal development and virulence because they regulate gene expression, filamentation, host association and invasion, pathogen stress response and survival. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis by which a growing number of amphipathic but structurally unrelated compounds elicit antifungal activity. Included in this group is carvacrol, a terpenoid phenol that is a prominent component of oregano and other plant essential oils. Carvacrol triggers an early dose dependent Ca2+ burst and long lasting pH changes in the model yeast S. cerevisiae. The distinct phases of ionic transients and a robust transcriptional response that overlaps with Ca2+ stress and nutrient starvation point to specific signaling events elicited by plant terpenoid phenols, rather than a non-specific lesion of the membrane as was previously considered. We discuss the potential use of plant essential oils and other agents that disrupt ion signaling pathways as chemosensitizers to augment conventional antifungal therapy, and to convert fungistatic drugs with strong safety profiles into fungicides.
Full Text Available BACKGROUND: Bile acids are potentially toxic compounds and their levels of hepatic production, uptake and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per1(-/-/Per2(-/- (PERDKO mice disrupted normal bile acid control and resulted in hepatic cholestasis. Restricted feeding caused a dramatic, transient elevation in hepatic bile acid levels that was associated with activation of the xenobiotic receptors CAR and PXR and elevated serum aspartate aminotransferase (AST, indicative of liver damage. In the PERDKO mice, serum bile acid levels were elevated and the circadian expression of key bile acid synthesis and transport genes, including Cyp7A1 and NTCP, was lost. This was associated with blunted expression of a primary clock output, the transcription factor DBP, which transactivates the promoters of both genes. CONCLUSIONS/SIGNIFICANCE: We conclude that disruption of the circadian clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease.
Dalton, Victoria S; Kolshus, Erik; McLoughlin, Declan M
Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD). PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant". There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action. As a narrative review, the current report was interpretive and qualitative in nature. Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression. © 2013 Published by Elsevier B.V.
Geeraerts, Sanne Barbara; Deutz, Marike Hester Francisca; Deković, Maja; Bunte, Tessa; Schoemaker, Kim; Espy, Kimberly Andrews; Prinzie, Peter; van Baar, Anneloes; Matthys, Walter
Children with concurrent impairments in regulating affect, behavior, and cognition can be identified with the Anxious/Depressed, Aggressive Behavior, and Attention Problems scales (or AAA scales) of the Child Behavior Checklist (CBCL). Jointly, these scales form the Dysregulation Profile (DP). Despite persuasive evidence that DP is a marker for severe developmental problems, no consensus exists on the preferred conceptualization and operationalization of DP in preschool years. We addressed this concern by testing and validating the factor structure of DP in a group of predominantly clinically referred preschool children. Participants were 247 children (195 boys and 52 girls), aged 3.5 to 5.5 years. Children were assessed at baseline and 18 months later, using parent and teacher reports, a clinical interview with parents, behavioral observations, and neuropsychological tasks. Confirmatory factor analysis showed that a bifactor model, with a general DP factor and 3 specific factors representing the AAA scales, fitted the data better than a second-order model and a one-factor model for both parent-reported and teacher-reported child problem behavior. Criterion validity analyses showed that the DP factor was concurrently and longitudinally associated with markers of dysregulation and clinically relevant criteria, whereas the specific factors representing the AAA scales were more differentially related to those criteria. DP is best conceptualized as a broad syndrome of dysregulation that exists in addition to the specific syndromes as represented by the AAA scales. Implications for researchers and clinicians are discussed. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
Epigenetics is a rapidly evolving scientific field of inquiry examining how a wide range of environmental, social, and nutritional exposures can dramatically control how genes are expressed without changing the underlying DNA. Research has demonstrated that epigenetics plays a large role in human development and in disease causation. In a sense, epigenetics blurs the distinction between "nature" and "nurture" as experiences (nurture) become a part of intrinsic biology (nature). Remarkably, some epigenetic modifications are durable across generations, meaning that exposures from our grandparents' generation might affect our health now, even if we have not experienced the same exposures. In the same vein, current exposures could affect the health of not only individuals currently living but also future generations. Given the relative novelty of epigenetics research and the multifactorial nature of human development and disease causation, it is unlikely that conclusive proof can be established showing that particular exposures lead to epigenetic risks that manifest into specific conditions. Using the Capabilities Approach ("CA") developed by Amartya Sen and Martha Nussbaum, this article argues that epigenetic risk is not merely a medical issue, but that it more generally implicates the underlying fairness and justice of our social contract. For instance, how we develop mentally or physically has a tremendous impact upon our inherent capabilities and our set of life options. The CA prompts us to ask questions such as: (1) what impact do particular epigenetic risks have on our ability to exercise free choices; (2) are these risks avoidable; and (3) how are these risks distributed across society? Due to the complex nature of epigenetic risk, tort law is predictably incapable of addressing this harm. Further, while regulatory agencies possess the statutory authority to begin addressing epigenetic harms, currently these agencies are not attuned to measure or to respond to
Characterization of the epigenetic profile of humans since the initial breakthrough on the human genome project has strongly established the key role of histone modifications and DNA methylation. These dynamic elements interact to determine the normal level of expression or methylation status of the constituent genes in the genome. Recently, considerable evidence has been put forward to demonstrate that environmental stress implicitly alters epigenetic patterns causing imbalance that can lead to cancer initiation. This chain of consequences has motivated attempts to computationally model the influence of histone modification and DNA methylation in gene expression and investigate their intrinsic interdependency. In this paper, we explore the relation between DNA methylation and transcription and characterize in detail the histone modifications for specific DNA methylation levels using a stochastic approach.
Schaefer, Anne; Tarakhovsky, Alexander; Greengard, Paul
Mental retardation is a common form of cognitive impairment affecting approximately 3% of the population in industrialized countries. The mental retardation syndrome incorporates a highly diverse group of mental disorders characterized by the combination of cognitive impairment and defective adaptive behavior. The genetic basis of the disease is strongly supported by identification of the genetic lesions associated with impaired cognition, learning, and social adaptation in many mental retardation syndromes. Several of the impaired genes encode epigenetic regulators of gene expression. These regulators exert their function through genome-wide posttranslational modification of histones or by mediating and/or recognizing DNA methylation. In this chapter, we review the most recent advances in the field of epigenetic mechanisms of mental retardation. In particular, we focus on animal models of the human diseases and the mechanism of transcriptional deregulation associated with changes in the cell epigenome.
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.
Ruth A. Lanius
Full Text Available The newly proposed criteria for posttraumatic stress disorder (PTSD in the Diagnostic and Statistical Manual (DSM-V include dysregulation of a variety of emotional states including fear, anger, guilt, and shame, in addition to dissociation and numbing. Consistent with these revisions, we postulate two models of emotion dysregulation in PTSD in which fear is not the prevailing emotion but is only one of several components implicated in a dysregulated emotional system that also mediates problems regulating anger, guilt, shame, dissociation, and numbing.We discuss whether there is a relationship between fear and other emotion regulation systems that may help further our understanding of PTSD and its underlying neurocircuitry. Two pathways describing the relationship between fear and other emotion regulation systems in PTSD are proposed. The first pathway describes emotion dysregulation as an outcome of fear conditioning through stress sensitization and kindling. The second pathway views emotion dysregulation as a distal vulnerability factor and hypothesizes a further exacerbation of fear and other emotion regulatory problems, including the development of PTSD after exposure to one or several traumatic event(s later in life. Future research and treatment implications are discussed.
prognostic markers for biochemical recurrence among prostate cancer patients with clinically localized disease. Epigenetics, 2006. 1(4): p. 183-6. 6...32. Zhao, H., et al., CpG methylation at promoter site -140 inactivates TGFbeta2 receptor gene in prostate cancer. Cancer, 2005. 104(1): p. 44-52...5]: taxis GO:0006935 : chemotaxis GO:0001525 : angiogenesis GO:0007155 : cell adhesion GO:0030155 : regulation of cell adhesion GO:0006954
Kulak, Anita; Steullet, Pascal; Cabungcal, Jan-Harry
Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due...
Wang, Junjun; Wu, Zhenlong; Li, Defa; Li, Ning; Dindot, Scott V; Satterfield, M Carey; Bazer, Fuller W; Wu, Guoyao
Epidemiological and animal studies have demonstrated a close link between maternal nutrition and chronic metabolic disease in children and adults. Compelling experimental results also indicate that adverse effects of intrauterine growth restriction on offspring can be carried forward to subsequent generations through covalent modifications of DNA and core histones. DNA methylation is catalyzed by S-adenosylmethionine-dependent DNA methyltransferases. Methylation, demethylation, acetylation, and deacetylation of histone proteins are performed by histone methyltransferase, histone demethylase, histone acetyltransferase, and histone deacetyltransferase, respectively. Histone activities are also influenced by phosphorylation, ubiquitination, ADP-ribosylation, sumoylation, and glycosylation. Metabolism of amino acids (glycine, histidine, methionine, and serine) and vitamins (B6, B12, and folate) plays a key role in provision of methyl donors for DNA and protein methylation. Disruption of epigenetic mechanisms can result in oxidative stress, obesity, insulin resistance, diabetes, and vascular dysfunction in animals and humans. Despite a recognized role for epigenetics in fetal programming of metabolic syndrome, research on therapies is still in its infancy. Possible interventions include: 1) inhibition of DNA methylation, histone deacetylation, and microRNA expression; 2) targeting epigenetically disturbed metabolic pathways; and 3) dietary supplementation with functional amino acids, vitamins, and phytochemicals. Much work is needed with animal models to understand the basic mechanisms responsible for the roles of specific nutrients in fetal and neonatal programming. Such new knowledge is crucial to design effective therapeutic strategies for preventing and treating metabolic abnormalities in offspring born to mothers with a previous experience of malnutrition.
Singh, Kuljeet; Erdman, Richard A; Swanson, Kara M; Molenaar, Adrian J; Maqbool, Nauman J; Wheeler, Thomas T; Arias, Juan A; Quinn-Walsh, Erin C; Stelwagen, Kerst
It is well established that milk production of the dairy cow is a function of mammary epithelial cell (MEC) number and activity and that these factors can be influenced by diverse environmental influences and management practises (nutrition, milk frequency, photoperiod, udder health, hormonal and local effectors). Thus, understanding how the mammary gland is able to respond to these environmental cues provides a huge potential to enhance milk production of the dairy cow. In recent years our understanding of molecular events within the MEC underlying bovine lactation has been advanced through mammary microarray studies and will be further advanced through the recent availability of the bovine genome sequence. In addition, the potential of epigenetic regulation (non-sequence inheritable chemical changes in chromatin, such as DNA methylation and histone modifications, which affect gene expression) to manipulate mammary function is emerging. We propose that a substantial proportion of unexplained phenotypic variation in the dairy cow is due to epigenetic regulation. Heritability of epigenetic marks also highlights the potential to modify lactation performance of offspring. Understanding the response of the MEC (cell signaling pathways and epigenetic mechanisms) to external stimuli will be an important prerequisite to devising new technologies for maximising their activity and, hence, milk production in the dairy cow.
Ramos, Yolande F M; Meulenbelt, Ingrid
The purpose of this review is to provide an update of recent advances in the established role of different layers of epigenetic control mechanism that are used by joint cells to ensure tissue homeostasis and cope with changing microenvironment (e.g. ageing or disease). New studies have further strengthened the evidence that joint tissue cells highly dependent on epigenetic control mechanisms, such as methylation at CpG-sites, noncoding RNAs and histone modifications to assure phenotypic plasticity and respective tissue homeostasis. Advancements towards high-dimensional molecular profiles and functional follow-up studies have started to uncover the complexity of these interacting networks of control. These studies highlight that in time loosening of epigenetic control increase the propensity of joint tissues to engage an osteoarthritis disease phenotype. Identification of changes in epigenetically regulated control mechanisms in joint tissues has provided novel insight into underlying mechanism of ongoing osteoarthritis disease pathophysiology. Such insight is crucial to enable development of evidence-based therapeutic options.
Hardy, Timothy; Mann, Derek A
Knowledge of the fundamental epigenetic mechanisms governing gene expression and cellular phenotype are sufficiently advanced that novel insights into the epigenetic control of chronic liver disease are now emerging. Hepatologists are in the process of shedding light on the roles played by DNA methylation, histone/chromatin modifications and non-coding RNAs in specific liver pathologies. Alongside these discoveries are advances in the technologies for the detection and quantification of epigenetic biomarkers, either directly from patient tissue or from body fluids. The premise for this review is to survey the recent advances in the field of liver epigenetics and to explore their potential for translation by industry and clinical hepatologists for the design of novel therapeutics and diagnostic/prognostic biomarkers. In particular, we present findings in the context of hepatocellular carcinoma, fibrosis and non-alcoholic fatty liver disease, where there is urgent unmet need for new clinical interventions and biomarkers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Kim, Somi; Kaang, Bong-Kiun
Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms. PMID:28082740
Allopolyploid speciation is widespread in plants, yet the molecular requirements for successful orchestration of coordinated gene expression for two divergent and reunited genomes are poorly understood. Recent studies in several plant systems have revealed that allopolyploid genesis under both synthetic and natural conditions often is accompanied by rapid and sometimes evolutionarily conserved epigeuetic changes, including alteration in cytosine methylation patterns, rapid silencing in ribosomal RNA and proteincoding genes, and de-repression of dormant transposable elements. These changes are inter-related and likely arise from chromatin remodeling and its effects on epigenetic codes during and subsequent to allopolyploid formation. Epigenetic modifications could produce adaptive epimutations and novel phenotypes, some of which may be evolutionarily stable for millions of years, thereby representing a vast reservoir of latent variation that may be episodically released and made visible to selection. This epigenetic variation may contribute to several important attributes of allopolyploidy, including functional diversification or subfunctionalization of duplicated genes, genetic and cytological diploidization, and quenching of incompatible inter-genomic interactions that are characteristic of allopolyploids. It is likely that the evolutionary success of allopolyploidy is in part attributatble to epigenetic phenomena that we are only just beginning to understand.
Full Text Available BACKGROUND: The pro-inflammatory cytokine interferon gamma (IFNγ, a key player in various neurological diseases, was recently shown to induce a dysregulated phenotype in neural stem/precursor cells (NSPCs that is characterized by the simultaneous expression of glial and neuronal markers and irregular electrophysiological properties. Thus far, the mechanisms of this phenomenon have remained unclear. METHODOLOGY/PRINCIPAL FINDINGS: To determine if binding of the signal transducers and activators of transcription (Stat 1 to the sonic hedgehog (SHH promoter is important for this phenomenon to occur, chromatin immunoprecipitation and pharmacological inhibition studies were performed. We report here that the activation of both the Stat 1 and SHH pathways is necessary to elicit the dysregulated phenotype. CONCLUSIONS/SIGNIFICANCE: Thus, blocking these pathways might preserve functional differentiation of NSPCs under inflammatory conditions leading to more effective regeneration.
Lowery, Aoife J
The involvement of miRNAs in the regulation of fundamental cellular functions has placed them at the fore of ongoing investigations into the processes underlying carcinogenesis. MiRNA expression patterns have been shown to be dysregulated in numerous human malignancies, including breast cancer, suggesting their probable involvement as novel classes of oncogenes or tumour suppressor genes. The identification of differentially expressed miRNAs and elucidation of their functional roles may provide insight into the complex and diverse molecular mechanisms of tumorigenesis. MiR-183 is located on chromosome 7q32 and is part of a miRNA family which are dysregulated in numerous cancers. The aims of this study were to further examine the expression and functional role of miR-183 in breast cancer.
Full Text Available Disinhibition caused by Cl- dysregulation is implicated in several neurological disorders. This form of disinhibition, which stems primarily from impaired Cl- extrusion through the co-transporter KCC2, is typically identified by a depolarizing shift in GABA reversal potential (EGABA. Here we show, using computer simulations, that intracellular [Cl-] exhibits exaggerated fluctuations during transient Cl- loads and recovers more slowly to baseline when KCC2 level is even modestly reduced. Using information theory and signal detection theory, we show that increased Cl- lability and settling time degrade neural coding. Importantly, these deleterious effects manifest after less KCC2 reduction than needed to produce the gross changes in EGABA required for detection by most experiments, which assess KCC2 function under weak Cl- load conditions. By demonstrating the existence and functional consequences of occult Cl- dysregulation, these results suggest that modest KCC2 hypofunction plays a greater role in neurological disorders than previously believed.
Tal, Reshef; Seifer, David B; Arici, Aydin
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in reproductive age affecting 5 to 7% of women. It is characterized by anovulatory infertility, hyperandrogenism, and polycystic ovaries. Angiogenesis in the ovary is critical for follicular growth, ovulation, and the subsequent development and regression of the corpus luteum. Accumulating evidence suggests that multiple angiogenic factors are dysregulated in PCOS, including vascular endothelial growth factor, angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. This angiogenic factor imbalance likely underlies the increased stromal vascularity observed in PCOS. Angiogenic factor dysregulation may play an important role in the pathophysiology of PCOS and may contribute to ovulatory dysfunction, subfertility, and ovarian hyperstimulation syndrome, which are commonly seen in women with PCOS. Further experimental studies are needed to gain a better understanding of the growth factors that are involved in normal and pathological ovarian angiogenesis, and to assess the potential of angiogenesis-based treatment strategies in PCOS.
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.
Miyake, Kunio; Hirasawa, Takae; Koide, Tsuyoshi; Kubota, Takeo
Autism was previously thought to be caused by environmental factors. However, genetic factors are now considered to be more contributory to the pathogenesis of autism, based on the recent findings of mutations in the genes which encode synaptic molecules associated with the communication between neurons. Epigenetic is a mechanism that controls gene expression without changing DNA sequence but by changing chromosomal histone modifications and its abnormality is associated with several neurodevelopmental diseases. Since epigenetic modifications are known to be affected by environmental factors such as nutrition, drugs and mental stress, autistic diseases are not only caused by congenital genetic defects, but may also be caused by environmental factors via epigenetic mechanism. In this chapter, we introduce autistic diseases caused by epigenetic failures and discuss epigenetic changes by environmental factors and discuss new treatments for neurodevelopmental diseases based on the recent epigenetic findings.
Strauss, Julius; Figg, William D
It has been known for decades that as cancer progresses, tumors develop genetic alterations, making them highly prone to developing resistance to therapies. Classically, it has been thought that these acquired genetic changes are fixed. This has led to the paradigm of moving from one cancer therapy to the next while avoiding past therapies. However, emerging data on epigenetic changes during tumor progression and use of epigenetic therapies have shown that epigenetic modifications leading to chemotherapy resistance have the potential to be reversible with epigenetic therapy. In fact, promising clinical data exist that treatment with epigenetic agents can diminish chemotherapy resistance in a number of tumor types including chronic myelogenous leukemia, colorectal, ovarian, lung and breast cancer. The potential for epigenetic-modifying drugs to allow for treatment of resistant disease is exciting and clinical trials have just begun to evaluate this area.
Cheng, Zhiyong; Almeida, Fabio A
The growing epidemic of type 2 diabetes mellitus (T2DM) and obesity is largely attributed to the current lifestyle of over-consumption and physical inactivity. As the primary platform controlling metabolic and energy homeostasis, mitochondria show aberrant changes in T2DM and obese subjects. While the underlying mechanism is under extensive investigation, epigenetic regulation is now emerging to play an important role in mitochondrial biogenesis, function, and dynamics. In line with lifestyle modifications preventing mitochondrial alterations and metabolic disorders, exercise has been shown to change DNA methylation of the promoter of PGC1α to favor gene expression responsible for mitochondrial biogenesis and function. In this article we discuss the epigenetic mechanism of mitochondrial alteration in T2DM and obesity, and the effects of lifestyle on epigenetic regulation. Future studies designed to further explore and integrate the epigenetic mechanisms with lifestyle modification may lead to interdisciplinary interventions and novel preventive options for mitochondrial alteration and metabolic disorders.
Epigenome refers to “epi” meaning outside the “genome.” Epigenetics is the field of study of the epigenome. Epigenetic modifications include changes in the promoter CpG Islands, modifications of histone protein structure, posttranslational repression by micro-RNA which contributes to the alteration of gene expression. Epigenetics provides an understanding of the role of gene-environment interactions on disease phenotype especially in complex multifactorial diseases. Periodontitis is a chronic...
Daphnia offer a variety of benefits for the study of epigenetics. Daphnia’s parthenogenetic life cycle allows the study of epigenetic effects in the absence of confounding genetic differences. Sex determination and sexual reproduction are epigenetically determined as are several other well-studied alternate phenotypes that arise in response to environmental stressors. Additionally, there is a large body of ecological literature available, recently complemented by the genome sequence of one sp...
Rival, Alain; Beulé, Thierry; Frédérique ABERLENC BERTOSSI; Tregear, James; Jaligot, Estelle
Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. In recent years, this field has attracted increasing attention as more epigenetic mechanisms affecting gene activity are being discovered. Such processes involve a complex interplay between DNA methylation, histone modifications, and non-coding RNAs, notably small interfering RNAs (siRNAs) and micro RNAs (miRNAs). Epigenetic regulation is not only important for generating differen...
Mirouze, Marie; Paszkowski, Jerzy
Plant epigenetics has recently gained unprecedented interest, not only as a subject of basic research but also as a possible new source of beneficial traits for plant breeding. We discuss here mechanisms of epigenetic regulation that should be considered when undertaking the latter. Since these mechanisms are responsible for the formation of heritable epigenetic gene variants (epialleles) and also regulate transposons mobility, both aspects could be exploited to broaden plant phenotypic and g...
Zengxiang Pan; Jinbi Zhang; Qifa Li; Yinxia Li; Fangxiong Shi; Zhuang Xie; Honglin Liu
During the growth and development of mammalian ovarian follicles,the activation and deactivation of mass genes are under the synergistic control of diverse modifiers through genetic and epigenetic events.Many factors regulate gene activity and functions through epigenetic modification without altering the DNA sequence,and the common mechanisms may include but arc not limited to: DNA methylation,histone modifications (e.g.,acetylation,deacetylation,phosphorylation,methylation,and ubiquitination),and RNA-associated silencing of gene expression by noncoding RNA.Over the past decade,substantial progress has been achieved in studies involving the epigenetic alterations during mammalian germ cell development.A number of candidate regulatory factors have been identified.This review focuses on the current available information of epigenetic alterations (e.g.,DNA methylation,histone modification,noncoding-RNA-mediated regulation) during mammalian folliculogenesis and recounts when and how epigenetic patterns are differentially established,maintained,or altered in this process.Based on different types of epigenetic regulation,our review follows the temporal progression of events during ovarian folliculogenesis and describes the epigenetic changes and their contributions to germ cell—specific functions at each stage (i.e.,primordial folliculogenesis (follicle formation),follicle maturation,and follicular atresia).
Nise, Melissa S; Falaturi, Puran; Erren, Thomas C
This paper provides information on the evolution of the 'epigenetics' concept since Aristotle and draws attention to the importance of epigenetic implications for cancer epidemiology in the years to come. Clearly, to understand origins of the concept of epigenetics, it is worthwhile to consider historical arguments associated with evolution. Equally clearly, in the last half of the 20th century, great advances in the understanding of epigenetics and, more specifically, great advances in the understanding of epigenetics in cancer have been made. However, reaping the full benefits of epigenetics lies beyond the predominant experimental studies of today. In general, epigenetics opens many doors in the field of cancer, but it also adds another level of complex, inter-related, and multi-dimensional information to research, and to its interpretation. Overall, future cancer studies should consider, or at least be sensitive to, epigenetic effects and mechanisms. Moving the focus beyond 'pristine' inheritance via DNA alone, cancer epidemiology investigating epigenetic exposures such as environmental factors (exposure to heavy metals, air pollution, arsenic and other toxins), dietary patterns (starvation, famine, contamination), and lifestyle habits (smoking, level of physical activity, and BMI) in populations has the prospect to significantly benefit future cancer prevention and treatment schemes.
Yamamuro, Chizuko; Zhu, Jian-Kang; Yang, Zhenbiao
The action of phytohormones in plants requires the spatiotemporal regulation of their accumulation and responses at various levels. Recent studies reveal an emerging relationship between the function of phytohormones and epigenetic modifications. In particular, evidence suggests that auxin biosynthesis, transport, and signal transduction is modulated by microRNAs and epigenetic factors such as histone modification, chromatin remodeling, and DNA methylation. Furthermore, some phytohormones have been shown to affect epigenetic modifications. These findings are shedding light on the mode of action of phytohormones and are opening up a new avenue of research on phytohormones as well as on the mechanisms regulating epigenetic modifications.
Zamudio, Natasha M; Chong, Suyinn; O'Bryan, Moira K
In recent years, it has become increasingly clear that epigenetic regulation of gene expression is critical during spermatogenesis. In this review, the epigenetic regulation and the consequences of its aberrant regulation during mitosis, meiosis and spermiogenesis are described. The current knowledge on epigenetic modifications that occur during male meiosis is discussed, with special attention on events that define meiotic sex chromosome inactivation. Finally, the recent studies focused on transgenerational and paternal effects in mice and humans are discussed. In many cases, these epigenetic effects resulted in impaired fertility and potentially long-ranging affects underlining the importance of research in this area.
Lester, Barry M; Conradt, Elisabeth; Marsit, Carmen
Epigenetics provides the opportunity to revolutionize our understanding of the role of genetics and the environment in explaining human behavior, although the use of epigenetics to study human behavior is just beginning. In this introduction, the authors present the basics of epigenetics in a way that is designed to make this exciting field accessible to a wide readership. The authors describe the history of human behavioral epigenetic research in the context of other disciplines and graphically illustrate the burgeoning of research in the application of epigenetic methods and principles to the study of human behavior. The role of epigenetics in normal embryonic development and the influence of biological and environmental factors altering behavior through epigenetic mechanisms and developmental programming are discussed. Some basic approaches to the study of epigenetics are reviewed. The authors conclude with a discussion of challenges and opportunities, including intervention, as the field of human behavioral epigenetics continue to grow. © 2016 The Authors. Child Development © 2016 Society for Research in Child Development, Inc.
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 Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD, yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1 is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD.
Natalie T. Y. Leung
Full Text Available Affective dysregulation is at the root of many psychopathologies, including stress induced disorders, anxiety disorders, and depression. The root of these disorders appears to be an attenuated, top-down cognitive control from the prefrontal cortices over the maladaptive subcortical emotional processing. A form of mental training, long-term meditation practice can trigger meditation-specific neuroplastic changes in the brain regions underlying cognitive control and affective regulation, suggesting that meditation can act as a kind of mental exercise to foster affective regulation and possibly a cost-effective intervention in mood disorders. Increasing research has suggested that the cultivation of awareness and acceptance along with a nonjudgmental attitude via meditation promotes adaptive affective regulation. This review examined the concepts of affective regulation and meditation and discussed behavioral and neural evidence of the potential clinical application of meditation. Lately, there has been a growing trend toward incorporating the “mindfulness” component into existing psychotherapeutic treatment. Promising results have been observed thus far. Future studies may consider exploring the possibility of integrating the element of “compassion” into current psychotherapeutic approaches.
Sharma, Sorabh; Taliyan, Rajeev
Huntington's disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Although, the exact underlying mechanism(s) leading to the neural cell death in HD still remains elusive, the transcriptional dysregulation is a major molecular feature. Recently, the transcriptional activation and repression regulated by chromatin acetylation has been found to be impaired in HD pathology. The acetylation and deacetylation of histone proteins is carried out by opposing actions of histone acetyl-transferases and histone deacetylases (HDACs), respectively. Studies carried out in cell culture, yeast, Drosophila and rodent model(s) have indicated that HDAC inhibitors (HDACIs) might provide useful class of therapeutic agents for HD. Clinical trials have also reported the beneficial effects of HDACIs in patients suffering from HD. Therefore, the development of HDACIs as therapeutics for HD has been vigorously pursued. In this review, we highlight and summarize the putative role of HDACs in HD like pathology and further discuss the potential of HDACIs as new therapeutic avenues for the treatment of HD. Copyright © 2015 Elsevier Ltd. All rights reserved.
Kalamohan, Kalaivani; Periasamy, Jayaprakash; Bhaskar Rao, Divya; Barnabas, Georgina D; Ponnaiyan, Srigayatri; Ganesan, Kumaresan
Despite the advancements in the cancer therapeutics, gastric cancer ranks as the second most common cancers with high global mortality rate. Integrative functional genomic investigation is a powerful approach to understand the major dysregulations and to identify the potential targets toward the development of targeted therapeutics for various cancers. Intestinal and diffuse type gastric tumors remain the major subtypes and the molecular determinants and drivers of these distinct subtypes remain unidentified. In this investigation, by exploring the network of gene coexpression association in gastric tumors, mRNA expressions of 20,318 genes across 200 gastric tumors were categorized into 21 modules. The genes and the hub genes of the modules show gastric cancer subtype specific expression. The expression patterns of the modules were correlated with intestinal and diffuse subtypes as well as with the differentiation status of gastric tumors. Among these, G1 module has been identified as a major driving force of diffuse type gastric tumors with the features of (i) enriched mesenchymal, mesenchymal stem cell like, and mesenchymal derived multiple lineages, (ii) elevated OCT1 mediated transcription, (iii) involvement of Notch activation, and (iv) reduced polycomb mediated epigenetic repression. G13 module has been identified as key factor in intestinal type gastric tumors and found to have the characteristic features of (i) involvement of embryonic stem cell like properties, (ii) Wnt, MYC and E2F mediated transcription programs, and (iii) involvement of polycomb mediated repression. Thus the differential transcription programs, differential epigenetic regulation and varying stem cell features involved in two major subtypes of gastric cancer were delineated by exploring the gene coexpression network. The identified subtype specific dysregulations could be optimally employed in developing subtype specific therapeutic targeting strategies for gastric cancer.
Zheng, Xiu-Deng; Tao, Yi
The evolutionary significance of the interaction between paternal and maternal genomes in fertilized zygotes is a very interesting and challenging question. Wang et al. developed the concept of epigenetic game theory, and they try to use this concept to explain the interaction between paternal and maternal genomes in fertilized zygotes . They emphasize that the embryogenesis can be considered as an ecological system in which two highly distinct and specialized gametes coordinate through either cooperation or competition, or both, to maximize the fitness of embryos under Darwinian selection. More specifically, they integrate game theory to model the pattern of coordination of paternal genome and maternal genomes mediated by DNA methylation dynamics, and they called this epigenetic game theory.
Buckley, Bethany A; Burkhart, Kirk B; Gu, Sam Guoping; Spracklin, George; Kershner, Aaron; Fritz, Heidi; Kimble, Judith; Fire, Andrew; Kennedy, Scott
Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.
Prattichizzo, Francesco; Giuliani, Angelica; Ceka, Artan; Rippo, Maria Rita; Bonfigli, Anna Rita; Testa, Roberto; Procopio, Antonio Domenico; Olivieri, Fabiola
The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to
Full Text Available Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i post-translation histone modification (i.e., deacetylation and methylation; (ii DNA global hypomethylation; (iii promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review.
Kaufman-Szymczyk, Agnieszka; Majewski, Grzegorz; Lubecka-Pietruszewska, Katarzyna; Fabianowska-Majewska, Krystyna
Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review.
Full Text Available Abstract Background Cancers, a group of multifactorial complex diseases, are generally caused by mutation of multiple genes or dysregulation of pathways. Identifying biomarkers that can characterize cancers would help to understand and diagnose cancers. Traditional computational methods that detect genes differentially expressed between cancer and normal samples fail to work due to small sample size and independent assumption among genes. On the other hand, genes work in concert to perform their functions. Therefore, it is expected that dysregulated pathways will serve as better biomarkers compared with single genes. Results In this paper, we propose a novel approach to identify dysregulated pathways in cancer based on a pathway interaction network. Our contribution is three-fold. Firstly, we present a new method to construct pathway interaction network based on gene expression, protein-protein interactions and cellular pathways. Secondly, the identification of dysregulated pathways in cancer is treated as a feature selection problem, which is biologically reasonable and easy to interpret. Thirdly, the dysregulated pathways are identified as subnetworks from the pathway interaction networks, where the subnetworks characterize very well the functional dependency or crosstalk between pathways. The benchmarking results on several distinct cancer datasets demonstrate that our method can obtain more reliable and accurate results compared with existing state of the art methods. Further functional analysis and independent literature evidence also confirm that our identified potential pathogenic pathways are biologically reasonable, indicating the effectiveness of our method. Conclusions Dysregulated pathways can serve as better biomarkers compared with single genes. In this work, by utilizing pathway interaction networks and gene expression data, we propose a novel approach that effectively identifies dysregulated pathways, which can not only be used
Green, Erin M; Gozani, Or
The rapid expansion of epigenetics research is fueled by the increasing understanding that epigenetic processes are critical to regulating cellular development and dysfunction of epigenetic programs is responsible for a diverse set of human pathologies, including cancer, autoimmune and neurodegenerative diseases. The expansive set of components contributing to epigenetic disease mechanisms and the often reversible nature of epigenetic lesions provide prime opportunities for the development of novel therapeutic strategies. Here, we provide an overview of epigenetics and its relationship to disease, discuss current epigenetics-based therapies and suggest new avenues for the identification of therapies targeting deregulated epigenetic programs in disease.
Ritter, David M; Zemel, Benjamin M; Hala, Tamara J; O'Leary, Michael E; Lepore, Angelo C; Covarrubias, Manuel
Spinal cord injury (SCI) patients develop chronic pain involving poorly understood central and peripheral mechanisms. Because dysregulation of the voltage-gated Kv3.4 channel has been implicated in the hyperexcitable state of dorsal root ganglion (DRG) neurons following direct injury of sensory nerves, we asked whether such a dysregulation also plays a role in SCI. Kv3.4 channels are expressed in DRG neurons, where they help regulate action potential (AP) repolarization in a manner that depends on the modulation of inactivation by protein kinase C (PKC)-dependent phosphorylation of the channel's inactivation domain. Here, we report that, 2 weeks after cervical hemicontusion SCI, injured rats exhibit contralateral hypersensitivity to stimuli accompanied by accentuated repetitive spiking in putative DRG nociceptors. Also in these neurons at 1 week after laminectomy and SCI, Kv3.4 channel inactivation is impaired compared with naive nonsurgical controls. At 2-6 weeks after laminectomy, however, Kv3.4 channel inactivation returns to naive levels. Conversely, Kv3.4 currents at 2-6 weeks post-SCI are downregulated and remain slow-inactivating. Immunohistochemistry indicated that downregulation mainly resulted from decreased surface expression of the Kv3.4 channel, as whole-DRG-protein and single-cell mRNA transcript levels did not change. Furthermore, consistent with Kv3.4 channel dysregulation, PKC activation failed to shorten the AP duration of small-diameter DRG neurons. Finally, re-expressing synthetic Kv3.4 currents under dynamic clamp conditions dampened repetitive spiking in the neurons from SCI rats. These results suggest a novel peripheral mechanism of post-SCI pain sensitization implicating Kv3.4 channel dysregulation and potential Kv3.4-based therapeutic interventions.
Szkop, Krzysztof J.; Cooke, Peter I. C.; Humphries, Joanne A.; Kalna, Viktoria; Moss, David S.; Schuster, Eugene F.; Nobeli, Irene
We present here the hypothesis that alternative poly-adenylation (APA) is dysregulated in the brains of individuals affected by Autism Spectrum Disorder (ASD), due to disruptions in the calcium signaling networks. APA, the process of selecting different poly-adenylation sites on the same gene, yielding transcripts with different-length 3′ untranslated regions (UTRs), has been documented in different tissues, stages of development and pathologic conditions. Differential use of poly-adenylation sites has been shown to regulate the function, stability, localization and translation efficiency of target RNAs. However, the role of APA remains rather unexplored in neurodevelopmental conditions. In the human brain, where transcripts have the longest 3′ UTRs and are thus likely to be under more complex post-transcriptional regulation, erratic APA could be particularly detrimental. In the context of ASD, a condition that affects individuals in markedly different ways and whose symptoms exhibit a spectrum of severity, APA dysregulation could be amplified or dampened depending on the individual and the extent of the effect on specific genes would likely vary with genetic and environmental factors. If this hypothesis is correct, dysregulated APA events might be responsible for certain aspects of the phenotypes associated with ASD. Evidence supporting our hypothesis is derived from standard RNA-seq transcriptomic data but we suggest that future experiments should focus on techniques that probe the actual poly-adenylation site (3′ sequencing). To address issues arising from the use of post-mortem tissue and low numbers of heterogeneous samples affected by confounding factors (such as the age, gender and health of the individuals), carefully controlled in vitro systems will be required to model the effect of calcium signaling dysregulation in the ASD brain. PMID:28955198
Several recent landmark papers describing N6-methyladenosine (m6A) RNA modifications have provided valuable new insights as to the importance of m6A in the RNA transcriptome and in furthering the understanding of RNA epigenetics. One endogenous enzyme responsible for demethylating RNA m6A, FTO, is highly expressed in the CNS and is likely involved in mRNA metabolism, splicing or other nuclear RNA processing events. microRNAs (miRNAs), a family of small, non-coding transcripts that bind to tar...
Full Text Available Stable molecular changes during cell division without any change in the sequence of DNA molecules is known as epigenetic. Molecular mechanisms involved in this process, including histone modifications, methylation of DNA, protein complex and RNA antisense. Cancer genome changes happen through a combination of DNA hypermethylation, long-term epigenetic silencing with heterozygosis loss and genomic regions loss. Different combinations of N-terminal’s changes cooperate with histone variants with a specific role in gene regulation. It have led to load a setting histone that determine transcription potential of a particular gene or genomic regions. DNA methylation analysis in genome region using methylation-specific digital karyotyping of normal breast tissue detect gene expression patterns and DNA specific methylation can be found in breast carcinoma too more than 100 genes in breast tumors or cell lines of breast cancer are reported hypermethylated. Important of DNA methylation on cancer has been concentrated CpG islands hypermethylation. Most of the techniques are able to identify hypermethylated areas. Often, methylated genes play important role in cell cycle regulation, apoptosis, metastasis and tissue invasion, angiogenesis and hormonal signaling. Cyclin D2 (CCND2 gene is an important regulator of cell cycle and increased of expression inhibits the transition from G1 to S cell cycle. This gene is frequently methylated in breast cancer and has been proposed as the first event. Other cell cycle regulator is p16ink4A / CDKN2A that methylated in a large number of human cancers, including breast cancer. Another regulator of the proliferation of breast cancer that methylated is tumor suppressor RAR-β cancer that has been found in lobular and ductal carcinoma. Recent studies have showed the role of epigenetic silencing in the pathogenesis of breast cancer in which tumor suppressor genes have been changed by acetylation and DNA deacetylation
Radulescu, Anca R; Rubin, Denis; Strey, Helmut H; Mujica-Parodi, Lilianne R
Theory and experimental evidence suggest that complex living systems function close to the boundary of chaos, with erroneous organization to an improper dynamical range (too stiff or chaotic) underlying system-wide dysregulation and disease. We hypothesized that erroneous organization might therefore also characterize paranoid schizophrenia, via optimization abnormalities in the prefrontal-limbic circuit regulating emotion. To test this, we acquired fMRI scans from 35 subjects (N = 9 patients with paranoid schizophrenia and N = 26 healthy controls), while they viewed affect-valent stimuli. To quantify dynamic regulation, we analyzed the power spectrum scale invariance (PSSI) of fMRI time-courses and computed the geometry of time-delay (Poincaré) maps, a measure of variability. Patients and controls showed distinct PSSI in two clusters (k(1) : Z = 4.3215, P = 0.00002 and k(2) : Z = 3.9441, P = 0.00008), localized to the orbitofrontal/medial prefrontal cortex (Brodmann Area 10), represented by β close to white noise in patients (β ≈ 0) and in the pink noise range in controls (β ≈ -1). Interpreting the meaning of PSSI differences, the Poincaré maps indicated less variability in patients than controls (Z = -1.9437, P = 0.05 for k(1) ; Z = -2.5099, P = 0.01 for k(2) ). That the dynamics identified Brodmann Area 10 is consistent with previous schizophrenia research, which implicates this area in deficits of working memory, executive functioning, emotional regulation and underlying biological abnormalities in synaptic (glutamatergic) transmission. Our results additionally cohere with a large body of work finding pink noise to be the normal range of central function at the synaptic, cellular, and small network levels, and suggest that patients show less supple responsivity of this region.
Gilbert SMITH, Michael G. RITCHIE
Full Text Available Speciation research has seen a renewed interest in ecological speciation, which emphasises divergent ecological selection leading to the evolution of reproductive isolation. Selection from divergent ecologies means that phenotypic plasticity can play an important role in ecological speciation. Phenotypic plasticity involves the induction of phenotypes over the lifetime of an organism and emerging evidence suggests that epigenetic marks such as cytosine and protein (histone modifications might regulate such environmental induction. Epigenetic marks play a wide role in a variety of processes including development, sex differentiation and allocation, sexual conflict, regulation of transposable elements and phenotypic plasticity. Here we describe recent studies that investigate epigenetic mechanisms in a variety of contexts. There is mounting evidence for environmentally induced epigenetic variation and for the stable inheritance of epigenetic marks between generations. Thus, epigenetically-based phenotypic plasticity may play a role in adaptation and ecological speciation. However, there is less evidence for the inheritance of induced epigenetic variation across multiple generations in animals. Currently few studies of ecological speciation incorporate the potential for the involvement of epigenetically-based induction of phenotypes, and we argue that this is an important omission [Current Zoology 59 (5: 686-696, 2013 ].
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.
Vandegehuchte, Michiel B; Janssen, Colin R
Epigenetics is the study of mitotically or meiotically heritable changes in gene function that occur without a change in the DNA sequence. Interestingly, epigenetic changes can be triggered by environmental factors. Environmental exposure to e.g. metals, persistent organic pollutants or endocrine disrupting chemicals has been shown to modulate epigenetic marks, not only in mammalian cells or rodents, but also in environmentally relevant species such as fish or water fleas. The associated changes in gene expression often lead to modifications in the affected organism's phenotype. Epigenetic changes can in some cases be transferred to subsequent generations, even when these generations are no longer exposed to the external factor which induced the epigenetic change, as observed in a study with fungicide exposed rats. The possibility of this phenomenon in other species was demonstrated in water fleas exposed to the epigenetic drug 5-azacytidine. This way, populations can experience the effects of their ancestors' exposure to chemicals, which has implications for environmental risk assessment. More basic research is needed to assess the potential phenotypic and population-level effects of epigenetic modifications in different species and to evaluate the persistence of chemical exposure-induced epigenetic effects in multiple subsequent generations.
This chapter reviews the major advances in the field of epigenetics as well as the environmental impacts of cattle. Many findings from our own research endeavors related to the topic of this chapter are also introduced. The phenotypic characterization of an animal can be changed through epigenetic ...
In the post genome era, the focus has shifted to understanding the mechanisms that regulate the interpretation of the genetic code. "Epigenetics" as a research field is taking center stage. Epigenetics is a term which is now being used throughout the scientific community in different contexts from p...
Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V
Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cutting-edge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy.
Besides genetics, also epigenetics can play a role in shaping the characteristics of a plant (phenotype). Epigenetics refers to chemical modifications of DNA and proteins associated with the DNA that can influence gene activity (the ‘epigenome’) and can be passed on through cell divisions and follow
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.
Full Text Available Cancer is nowadays considered to be both a genetic and an epigenetic disease. The most well studied epigenetic modification in humans is DNA methylation; however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather is linked to other modifications, such as histone modifications. Epigenetic abnormalities are reversible and as a result novel therapies that work by reversing epigenetic effects are being increasingly explored. The biggest clinical impact of epigenetic modifying agents in neoplastic disorders thus far has been in haematological malignancies, and the efficacy of DNMT inhibitors and HDAC inhibitors in blood cancers clearly attests to the principle that therapeutic modification of the cancer cell epigenome can produce clinical benefit. This paper will discuss the most well studied epigenetic modifications and how these are linked to cancer, will give a brief overview of the clinical use of epigenetics as biomarkers, and will focus in more detail on epigenetic drugs and their use in solid and blood cancers.
Karki, Pratap; Smith, Keisha; Johnson, James; Aschner, Michael; Lee, Eunsook Y
Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 (glutamate transporter 1 and glutamate aspartate transporter in rodents, respectively), are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.
Karki, Pratap; Smith, Keisha; Johnson, James; Aschner, Michael; Lee, Eunsook
Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 [glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) in rodents, respectively], are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms (SNPs) and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via NF-κB and CREB at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 (YY1) plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics, and translational regulation of EAAT2. PMID:25064045
Primary immunodeficiencies (PIDs) are a group of rare genetic diseases resulting in the impairment of one or more functions of the human immune system. Common variable immunodeficiency (CVID) is one of the most prevalent PIDs, yet despite extensive genetic analysis, most patients do not have a monogenetic diagnosis. This has led to the theory that CVID must be a polygenetic condition. An alternative theory to a monogenetic or polygenetic underlying cause of CVID is that it is epigenetic phenomena that are causal in the majority of CVID patients. I will briefly discuss epigenetic regulation in B-cell biology and development, current examples of epigenetic diseases causing CVID-like primary antibody deficiencies, and how these observations may guide future investigation into the role of epigenetics in CVID.
Mervat Y. Hanafi
Full Text Available Background. Intrauterine environment plays a pivotal role in the origin of fatal diseases such as diabetes. Diabetes and obesity are associated with low-grade inflammatory state and dysregulated adipokines production. This study aims to investigate the effect of maternal obesity and malnutrition on adipokines production (adiponectin, leptin, and TNF-α in F1 offspring in rats. Materials and Methods. Wistar rats were allocated in groups: F1 offspring of control mothers under control diet (CF1-CD and under high-fat diet (CF1-HCD, F1 offspring of obese mothers under CD (OF1-CD and under HCD (OF1-HCD, and F1 offspring of malnourished mothers under CD (MF1-CD and under HCD (MF1-HCD. Every 5 weeks postnatally, blood samples were obtained for biochemical analysis. Results. At the end of the 30-week follow-up, OF1-HCD and MF1-HCD exhibited hyperinsulinemia, moderate dyslipidemia, insulin resistance, and impaired glucose homeostasis compared to CF1-CD and CF1-HCD. OF1-HCD and MF1-HCD demonstrated low serum levels of adiponectin and high levels of leptin compared to CF1-CD and CF1-HCD. OF1-CD, OF1-HCD, and MF1-HCD had elevated serum levels of TNF-α compared to CF1-CD and CF1-HCD (p<0.05. Conclusion. Maternal nutritional manipulation predisposes the offspring to development of insulin resistance in their adult life, probably via instigating dysregulated adipokines production.
Kimberly R. Shorter
Full Text Available Deer mice (Peromyscus offer an opportunity for studying the effects of natural genetic/epigenetic variation with several advantages over other mammalian models. These advantages include the ability to study natural genetic variation and behaviors not present in other models. Moreover, their life histories in diverse habitats are well studied. Peromyscus resources include genome sequencing in progress, a nascent genetic map, and >90,000 ESTs. Here we review epigenetic studies and relevant areas of research involving Peromyscus models. These include differences in epigenetic control between species and substance effects on behavior. We also present new data on the epigenetic effects of diet on coat-color using a Peromyscus model of agouti overexpression. We suggest that in terms of tying natural genetic variants with environmental effects in producing specific epigenetic effects, Peromyscus models have a great potential.
Yang, Pinglin; He, Xijing; Malhotra, Anshoo
Interest in dietary polyphenols has recently increased greatly owing to their antioxidant capacity and their possible beneficial implications in various pathological states, including cancer. Polyphenols are a group of chemicals found in many fruits, vegetables, and plants and have the ability to remove free radicals from the body. In the last 2 decades, the numbers of reports on the potential health benefits of polyphenols have increased. This review provides the available scientific data that justify importance of polyphenols in correlation with epigenetics to fight against carcinogenesis. Epigenetics involves genetic control by mechanisms other than DNA sequence. These epigenetic mechanisms have ability to switch on or off various important genes influencing the process of cancer. Furthermore, due to the reversible nature of these epigenetic mechanisms, they are influenced by a variety of dietary polyphenols. This review focuses on the dietary polyphenols that significantly affect these epigenetic mechanisms to mitigate carcinogenesis.
Kami D. M. Harris
Full Text Available Daphnia offer a variety of benefits for the study of epigenetics. Daphnia’s parthenogenetic life cycle allows the study of epigenetic effects in the absence of confounding genetic differences. Sex determination and sexual reproduction are epigenetically determined as are several other well-studied alternate phenotypes that arise in response to environmental stressors. Additionally, there is a large body of ecological literature available, recently complemented by the genome sequence of one species and transgenic technology. DNA methylation has been shown to be altered in response to toxicants and heavy metals, although investigation of other epigenetic mechanisms is only beginning. More thorough studies on DNA methylation as well as investigation of histone modifications and RNAi in sex determination and predator-induced defenses using this ecologically and evolutionarily important organism will contribute to our understanding of epigenetics.
Matzen, Sara Maj Hyldig; Croxall, Nicola; Contreras, David A.
BACKGROUND: Epigenetic reprogramming is critical for genome regulation during germ line development. Genome-wide demethylation in mouse primordial germ cells (PGC) is a unique reprogramming event essential for erasing epigenetic memory and preventing the transmission of epimutations to the next...... an increased proportion of cells in G2. CONCLUSIONS: Our study demonstrates that epigenetic reprogramming occurs in pig migratory and gonadal PGC, and establishes the window of time for the occurrence of these events. Reprogramming of histone H3K9me2 and H3K27me3 detected between E15-E21 precedes the dynamic...... DNA demethylation at imprinted loci and DNA repeats between E22-E42. Our findings demonstrate that major epigenetic reprogramming in the pig germ line follows the overall dynamics shown in mice, suggesting that epigenetic reprogramming of germ cells is conserved in mammals. A better understanding...
Tan, Qihua; Heijmans, Bastiaan T; Hjelmborg, Jacob V B
BACKGROUND: Current epigenetic studies on aging are dominated by the cross-sectional design that correlates subjects' ages or age groups with their measured epigenetic profiles. Such studies have been more aimed at age prediction or building up the epigenetic clock of age rather than focusing...... on the dynamic patterns in epigenetic changes during the aging process. METHODS: We performed an epigenome-wide association study of intra-individual longitudinal changes in DNA methylation at CpG (cytosine-phosphate-guanine) sites measured in whole-blood samples of a cohort of 43 elderly twin pairs followed......-wide association studies on a cohort of old twins followed up for 10 years identified highly replicable epigenetic biomarkers predominantly implicated in signalling pathways of degenerative disorders and survival in the elderly....
Qureshi, Irfan A; Mehler, Mark F
The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection. Copyright © 2015 Elsevier B.V. All rights reserved.
Huang, Biao; Jiang, Cizhong; Zhang, Rongxin
Epigenetics is one of the most rapidly developing fields of biological research. Breakthroughs in several technologies have enabled the possibility of genome-wide epigenetic research, for example the mapping of human genome-wide DNA methylation. In addition, with the development of various high-throughput and high-resolution sequencing technologies, a large number of functional noncoding RNAs have been identified. Massive studies indicated that these functional ncRNA also play an important role in epigenetics. In this review, we gain inspiration from the recent proposal of the ceRNAs hypothesis. This hypothesis proposes that miRNAs act as a language of communication. Accordingly, we further deduce that all of epigenetics may functionally acquire such a unique language characteristic. In summary, various epigenetic markers may not only participate in regulating cellular processes, but they may also act as the intracellular 'language' of communication and are involved in extensive information exchanges within cell.
Feng, Suhua; Jacobsen, Steven E; Reik, Wolf
Epigenetic modifications of the genome are generally stable in somatic cells of multicellular organisms. In germ cells and early embryos, however, epigenetic reprogramming occurs on a genome-wide scale, which includes demethylation of DNA and remodeling of histones and their modifications. The mechanisms of genome-wide erasure of DNA methylation, which involve modifications to 5-methylcytosine and DNA repair, are being unraveled. Epigenetic reprogramming has important roles in imprinting, the natural as well as experimental acquisition of totipotency and pluripotency, control of transposons, and epigenetic inheritance across generations. Small RNAs and the inheritance of histone marks may also contribute to epigenetic inheritance and reprogramming. Reprogramming occurs in flowering plants and in mammals, and the similarities and differences illuminate developmental and reproductive strategies.
Maes, Ken, E-mail: email@example.com; Menu, Eline; Van Valckenborgh, Els [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel (Belgium); Van Riet, Ivan [Stem Cell Laboratory, Department Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussel (Belgium); Vanderkerken, Karin; De Bruyne, Elke, E-mail: firstname.lastname@example.org [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel (Belgium)
Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.
Maes, Ken; Menu, Eline; Van Valckenborgh, Els; Van Riet, Ivan; Vanderkerken, Karin; De Bruyne, Elke
Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment. PMID:24216985
Takacs, Maria; Segesdi, Judit; Banati, Ferenc; Koroknai, Anita; Wolf, Hans; Niller, Hans Helmut; Minarovits, Janos
suggest that binding of EBNA1 to its cellular target sites may elicit local demethylation and contribute thereby to the activation of silent cellular promoters. EBNA2 interacts with histone acetyltransferases, and EBNALP (EBNA5) coactivates transcription by displacing histone deacetylase 4 from EBNA2-bound promoter sites. EBNA3C (EBNA6) seems to be associated both with histone acetylases and deacetylases, although in separate complexes. LMP1, a transmembrane protein involved in malignant transformation, can affect both alternative systems of epigenetic memory, DNA methylation and the Polycomb-trithorax group of protein complexes. In epithelial cells LMP1 can up-regulate DNA methyltransferases and, in Hodgkin lymphoma cells, induce the Polycomb group protein Bmi-1. In addition, LMP1 can also modulate cellular gene expression programs by affecting, via the NF-κB pathway, levels of cellular microRNAs miR-146a and miR-155. These interactions may result in epigenetic dysregulation and subsequent cellular dysfunctions that may manifest in or contribute to the development of pathological changes (e.g. initiation and progression of malignant neoplasms, autoimmune phenomena, immunodeficiency). Thus, Epstein-Barr virus, similarly to other viruses and certain bacteria, may induce pathological changes by epigenetic reprogramming of host cells. Elucidation of the epigenetic consequences of EBV-host interactions (within the framework of the emerging new field of patho-epigenetics) may have important implications for therapy and disease prevention, because epigenetic processes are reversible and continuous silencing of EBV genes contributing to patho-epigenetic changes may prevent disease development.
demethylation, we suggest that binding of EBNA1 to its cellular target sites may elicit local demethylation and contribute thereby to the activation of silent cellular promoters. EBNA2 interacts with histone acetyltransferases, and EBNALP (EBNA5 coactivates transcription by displacing histone deacetylase 4 from EBNA2-bound promoter sites. EBNA3C (EBNA6 seems to be associated both with histone acetylases and deacetylases, although in separate complexes. LMP1, a transmembrane protein involved in malignant transformation, can affect both alternative systems of epigenetic memory, DNA methylation and the Polycomb-trithorax group of protein complexes. In epithelial cells LMP1 can up-regulate DNA methyltransferases and, in Hodgkin lymphoma cells, induce the Polycomb group protein Bmi-1. In addition, LMP1 can also modulate cellular gene expression programs by affecting, via the NF-κB pathway, levels of cellular microRNAs miR-146a and miR-155. These interactions may result in epigenetic dysregulation and subsequent cellular dysfunctions that may manifest in or contribute to the development of pathological changes (e.g. initiation and progression of malignant neoplasms; autoimmune phenomena; immunodeficiency. Thus, Epstein-Barr virus, similarly to other viruses and certain bacteria, may induce pathological changes by epigenetic reprogramming of host cells. Elucidation of the epigenetic consequences of EBV-host interactions (within the framework of the emerging new field of patho-epigenetics may have important implications for therapy and disease prevention, because epigenetic processes are reversible and continuous silencing of EBV genes contributing to patho-epigenetic changes may prevent disease development.
Zoldoš, Vlatka; Grgurević, Srđana; Lauc, Gordan
Protein N-glycosylation is an ancient metabolic pathway that still exists in all three domains of life (Archaea, Bacteria and Eukarya). The covalent addition of one or more complex oligosaccharides (glycans) to protein backbones greatly diversifies their structures and makes the glycoproteome several orders of magnitude more complex than the proteome itself. Contrary to polypeptides, which are defined by a sequence of nucleotides in the corresponding genes, the glycan part of glycoproteins are encoded in a complex dynamic network of hundreds of proteins, whereby activity is defined by both genetic sequence and the regulation of gene expression. Owing to the complex nature of their biosynthesis, glycans are particularly versatile and apparently a large part of human variation derives from differences in protein glycosylation. Composition of the individual glycome appears to be rather stable, and thus differences in the pattern of glycan synthesis between individuals could originate either from genetic polymorphisms or from stable epigenetic regulation of gene expression in different individuals. Studies of epigenetic modification of genes involved in protein glycosylation are still scarce, but their results indicate that this process might be very important for the regulation of protein glycosylation.
Kanherkar, Riya R.; Stair, Susan E.; Bhatia-Dey, Naina; Mills, Paul J.; Chopra, Deepak
Since time immemorial humans have utilized natural products and therapies for their healing properties. Even now, in the age of genomics and on the cusp of regenerative medicine, the use of complementary and alternative medicine (CAM) approaches represents a popular branch of health care. Furthermore, there is a trend towards a unified medical philosophy referred to as Integrative Medicine (IM) that represents the convergence of CAM and conventional medicine. The IM model not only considers the holistic perspective of the physiological components of the individual, but also includes psychological and mind-body aspects. Justification for and validation of such a whole-systems approach is in part dependent upon identification of the functional pathways governing healing, and new data is revealing relationships between therapies and biochemical effects that have long defied explanation. We review this data and propose a unifying theme: IM's ability to affect healing is due at least in part to epigenetic mechanisms. This hypothesis is based on a mounting body of evidence that demonstrates a correlation between the physical and mental effects of IM and modulation of gene expression and epigenetic state. Emphasis on mapping, deciphering, and optimizing these effects will facilitate therapeutic delivery and create further benefits. PMID:28316635
Full Text Available Parathyroid cancers (PCas are rare malignancies representing approximately 0.005% of all cancers. PCas are a rare cause of primary hyperparathyroidism, which is the third most common endocrine disease, mainly related to parathyroid benign tumors. About 90% of PCas are hormonally active hypersecreting parathormone (PTH; consequently patients present with complications of severe hypercalcemia. Pre-operative diagnosis is often difficult due to clinical features shared with benign parathyroid lesions. Surgery provides the current best chance of cure, though persistent or recurrent disease occurs in about 50% of patients with PCas. Somatic inactivating mutations of CDC73/HRPT2 gene, encoding parafibromin, are the most frequent genetic anomalies occurring in PCas. Recently, the aberrant DNA methylation signature and microRNA expression profile have been identified in PCas, providing evidence that parathyroid malignancies are distinct entities from parathyroid benign lesions, showing an epigenetic signature resembling some embryonic aspects. The present paper reviews data about epigenetic alterations in PCas, up to now limited to DNA methylation, chromatin regulators and microRNA profile.
Wiklund, Erik Digman
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that negatively regulate gene expression post-transcriptionally by binding to complementary sequences in the 3’UTR of target mRNAs in the cytoplasm. However, recent evidence suggests that certain miRNAs are enriched in the nucleus......, and their targets do not seem restricted to mRNA 3’UTRs. Therefore, miRNAs are predicted to have a variety functions throughout mammalian cells. MiRNA genes appear to be regulated in much the same way as coding genes, but current insight into transcriptional miRNA control lacks detail, as mapping miRNA promoters...... and confirming transcriptional start sites can be difficult. Epigenetics, gene regulatory and DNA modification mechanisms not involving a change to the primary sequence, have been implied in the regulation of a number of miRNA loci. Both epigenetic and miRNA signatures are broadly altered in cancer...
Rowles, Joie; Wong, Morgan; Powers, Ryan; Olsen, Mark
Several recent landmark papers describing N(6) -methyladenosine (m(6) A) RNA modifications have provided valuable new insights as to the importance of m(6) A in the RNA transcriptome and in furthering the understanding of RNA epigenetics. One endogenous enzyme responsible for demethylating RNA m(6) A, FTO, is highly expressed in the CNS and is likely involved in mRNA metabolism, splicing or other nuclear RNA processing events. microRNAs (miRNAs), a family of small, non-coding transcripts that bind to target mRNAs and inhibit subsequent translation, are highly expressed in the CNS and are associated with several neurological disorders, including epilepsy. miRNAs frequently bind to recognition sequences in the 3'UTR, a region that is also enriched for m(6) A. Certain specific miRNAs are upregulated by neuronal activity and are coupled to epileptogenesis; these miRNAs contain a consensus m(6) A site that if methylated could possibly regulate miRNA processing or function. This commentary highlights aspects from recent papers to propose a functional association between FTO, RNA epigenetics and epilepsy.
Verdelli, Chiara; Corbetta, Sabrina
Parathyroid cancers (PCas) are rare malignancies representing approximately 0.005% of all cancers. PCas are a rare cause of primary hyperparathyroidism, which is the third most common endocrine disease, mainly related to parathyroid benign tumors. About 90% of PCas are hormonally active hypersecreting parathormone (PTH); consequently patients present with complications of severe hypercalcemia. Pre-operative diagnosis is often difficult due to clinical features shared with benign parathyroid lesions. Surgery provides the current best chance of cure, though persistent or recurrent disease occurs in about 50% of patients with PCas. Somatic inactivating mutations of CDC73/HRPT2 gene, encoding parafibromin, are the most frequent genetic anomalies occurring in PCas. Recently, the aberrant DNA methylation signature and microRNA expression profile have been identified in PCas, providing evidence that parathyroid malignancies are distinct entities from parathyroid benign lesions, showing an epigenetic signature resembling some embryonic aspects. The present paper reviews data about epigenetic alterations in PCas, up to now limited to DNA methylation, chromatin regulators and microRNA profile. PMID:28157158
Khan, Deena; Ahmed, S Ansar
Endocrine disrupting chemicals (EDC) abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical, and consumer product industries. Many of the EDCs such as Bisphenol A (BPA) have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth, and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation, and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight the BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non-lymphoid cells is emphasized. We recognize that most of these studies are on non-lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system.
Li, Xue; Song, Peige; Timofeeva, Maria; Meng, Xiangrui; Rudan, Igor; Little, Julian; Satsangi, Jack; Campbell, Harry; Theodoratou, Evropi
We provide a comprehensive field synopsis of genetic and epigenetic associations for paediatric Inflammatory Bowel Disease (IBD). A systematic review was performed and included 84 genetic association studies reporting data for 183 polymorphisms in 71 genes. Meta-analyses were conducted for 20 SNPs in 10 genes of paediatric Crohn’s disease (CD) and for 8 SNPs in 5 genes of paediatric ulcerative colitis (UC). Five epigenetic studies were also included, but formal meta-analysis was not possible. Venice criteria and Bayesian false discovery probability test were applied to assess the credibility of associations. Nine SNPs in 4 genes were considered to have highly credible associations with paediatric CD, of which four variants (rs2066847, rs12521868, rs26313667, rs1800629) were not previously identified in paediatric GWAS. Differential DNA methylation in NOD2 and TNF-α, dysregulated expression in let-7 and miR-124 were associated with paediatric IBD, but not as yet replicated. Highly credible SNPs associated with paediatric IBD have also been implicated in adult IBD, with similar magnitudes of associations. Early onset and distinct phenotypic features of paediatric IBD might be due to distinct epigenetic changes, but these findings need to be replicated. Further progress identifying genetic and epigenetic susceptibility of paediatric IBD will require international collaboration, population diversity and harmonization of protocols. PMID:27670835
Full Text Available Endocrine disrupting chemicals (EDC abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical and consumer product industries. Many of the EDCs such as Bisphenol A (BPA have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non-lymphoid cells is emphasized. We recognize that most of these studies are on non-lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system.
Claudio Napoli; Vincenzo Grimaldi; Maria Rosaria De Pascale; Linda Sommese; Teresa Infante; Andrea Soricelli
Epigenetic modifications include DNA methylation, his-tone modifications, and micro RNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of Cp G islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression(e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of micro RNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense micro RNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of eme-rging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols.
Burdge, Graham C; Lillycrop, Karen A
There is considerable evidence for induction of differential risk of noncommunicable diseases in humans by variation in the quality of the early life environment. Studies in animal models show that induction and stability of induced changes in the phenotype of the offspring involve altered epigenetic regulation by DNA methylation and covalent modifications of histones. These findings indicate that such epigenetic changes are highly gene specific and function at the level of individual CpG dinucleotides. Interventions using supplementation with folic acid or methyl donors during pregnancy, or folic acid after weaning, alter the phenotype and epigenotype induced by maternal dietary constraint during gestation. This suggests a possible means for reducing risk of induced noncommunicable disease, although the design and conduct of such interventions may require caution. The purpose of this review is to discuss recent advances in understanding the mechanism that underlies the early life origins of disease and to place these studies in a broader life-course context.
Marcinkiewicz, Katarzyna M.; Gudas, Lorraine J., E-mail: email@example.com
To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 mark on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC-9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes. - Highlights: • RNAseq elucidates differences between non-tumorigenic and tumorigenic oral keratinocytes. • Changes in HOX mRNA in SCC-9 vs. OKF6-TERT1R cells are a result of altered epigenetic regulation. • RNAseq shows that retinoic acid (RA) influences gene expression in both OKF6-TERT1R and SCC-9 cells.
Full Text Available Effective estimation of the salience of environmental stimuli underlies adaptive behaviour, while related aberrance is believed to undermine rational thought processes in schizophrenia. A network including bilateral frontoinsular cortex (FIC and dorsal anterior cingulate cortex (dACC has been observed to respond to salient stimuli using functional magnetic resonance imaging (fMRI. To test the hypothesis that activity in this salience network (SN is less discriminately modulated by contextually-relevant stimuli in schizophrenia than in healthy individuals, fMRI data were collected in 20 individuals with schizophrenia and 13 matched controls during performance of a modified monetary incentive delay task. After quantitatively identifying spatial components representative of the FIC and dACC features of the SN, two principal analyses were conducted. In the first, modulation of SN activity by salience was assessed by measuring response to trial outcome. First-level general linear models were applied to individual-specific time-courses of SN activity identified using spatial independent component analysis. This analysis revealed a significant salience-by-performance-by-group interaction on the best-fit FIC component’s activity at reward outcome, whereby healthy individuals but not individuals with schizophrenia exhibited significantly greater distinction between the response to hits and misses in high salience trials than in low salience trials. The second analysis aimed to ascertain whether SN component amplitude differed between the study groups over the duration of the experiment. Independent-samples T-tests on back-projected, percent-signal-change scaled SN component images importantly showed that the groups did not differ in the overall amplitude of SN expression over the entire dataset. These findings of dysregulated but not decreased SN activity in schizophrenia provide physiological support for mechanistic conceptual frameworks of delusional
White, Thomas P.; Gilleen, James; Shergill, Sukhwinder S.
Effective estimation of the salience of environmental stimuli underlies adaptive behavior, while related aberrance is believed to undermine rational thought processes in schizophrenia. A network including bilateral frontoinsular cortex (FIC) and dorsal anterior cingulate cortex (dACC) has been observed to respond to salient stimuli using functional magnetic resonance imaging (fMRI). To test the hypothesis that activity in this salience network (SN) is less discriminately modulated by contextually-relevant stimuli in schizophrenia than in healthy individuals, fMRI data were collected in 20 individuals with schizophrenia and 13 matched controls during performance of a modified monetary incentive delay (MID) task. After quantitatively identifying spatial components representative of the FIC and dACC features of the SN, two principal analyses were conducted. In the first, modulation of SN activity by salience was assessed by measuring response to trial outcome. First-level general linear models were applied to individual-specific time-courses of SN activity identified using spatial independent component analysis (ICA). This analysis revealed a significant salience-by-performance-by-group interaction on the best-fit FIC component's activity at trial outcome, whereby healthy individuals but not individuals with schizophrenia exhibited greater distinction between the response to hits and misses in high salience trials than in low salience trials. The second analysis aimed to ascertain whether SN component amplitude differed between the study groups over the duration of the experiment. Independent-samples T-tests on back-projected, percent-signal-change scaled SN component images importantly showed that the groups did not differ in the overall amplitude of SN expression over the entire dataset. These findings of dysregulated but not decreased SN activity in schizophrenia provide physiological support for mechanistic conceptual frameworks of delusional thought formation
Developmental plasticity, the capacity of a single genotype to give rise to different phenotypes, affects evolutionary dynamics by influencing the rate and direction of phenotypic change. It is based on regulatory changes in gene expression and gene products, which are partially controlled by epigenetic mechanisms. Plasticity involves not just epigenetic changes in somatic cells and tissues; it can also involve changes in germline cells. Germline epigenetic plasticity increases evolvability, the capacity to generate heritable, selectable, phenotypic variations, including variations that lead to novel functions. I discuss studies that show that some complex adaptive responses to new challenges are mediated by germline epigenetic processes, which can be transmitted over variable number of generations, and argue that the heritable variations that are generated epigenetically have an impact on both small-scale and large-scale aspects of evolution. First, I review some recent ecological studies and models that show that germline (gametic) epigenetic inheritance can lead to cumulative micro-evolutionary changes that are rapid and semi-directional. I suggest that "priming" and "epigenetic learning" may be of special importance in generating heritable, fine-tuned adaptive responses in populations. Second, I consider work showing how genomic and environmental stresses can also lead to epigenome repatterning, and produce changes that are saltational.
Hou, Lifang; Zhang, Xiao; Wang, Dong; Baccarelli, Andrea
Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes. PMID:22253299
Significance: Epigenetics involves alterations in gene expression without changing the nucleotide sequence. Because some epigenetic changes can be reversed chemically, epigenetics has tremendous implications for disease intervention and treatment. Recent Advances: After epigenetic components in cancer were characterized, genes and pathways are being characterized in other diseases such as diabetes, obesity, and neurological disorders. Observational, experimental, and clinical studies in diffe...
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.
Herceg, Zdenko; Vaissière, Thomas
Although epidemiological studies support the role of environment in a wide range of human cancers, the precise mechanisms by which environmental exposures promote cancer development and progression remain poorly understood. Environmental factors have been proposed to promote the development of malignancies by eliciting epigenetic changes; however, it is only with recent advances in epigenetics and epigenomics that target genes and the mechanisms underlying environmental influences are beginning to be elucidated. Because epigenetic mechanisms may function as an interface between environmental factors and the genome, deregulation of the epigenome by environmental stressors is likely to disrupt different cellular processes and contribute to cancer risk. In addition, the early appearance and ubiquity of epigenetic changes in virtually all steps of tumor development and progression in most, if not all, human neoplasms, make them attractive targets for biomarker discovery and targeted prevention. At the cellular level, aberrant epigenetic changes associated with environmental exposures may deregulate key cellular processes (including transcriptional control, DNA repair, cell cycle control, and carcinogen detoxification), which can be further modulated by environmental stressors, thus defining not only the phenotype of the disease but also potential biomarkers. This review summarizes recent progress in our understanding of the epigenetic mechanisms through which environmental factors may promote tumor development, with a particular focus on human lung cancer.
Full Text Available Post-traumatic stress disorder (PTSD is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior. In this review, we discuss the current evidence for epigenetic regulation of PTSD in human studies and in animal models and comment on ways in which these models can be expanded. In addition, we identify key outstanding questions in the study of epigenetic mechanisms of PTSD in the context of rapidly evolving technologies that are constantly updating and adjusting our understanding of epigenetic modifications and their functional roles. Finally, we discuss the potential application of epigenetic approaches in identifying markers of risk and resilience that can be utilized to promote early intervention and develop therapeutic strategies to combat PTSD after symptom onset.
Zovkic, Iva B; Meadows, Jarrod P; Kaas, Garrett A; Sweatt, J David
Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior. In this review, we discuss the current evidence for epigenetic regulation of PTSD in human studies and in animal models and comment on ways in which these models can be expanded. In addition, we identify key outstanding questions in the study of epigenetic mechanisms of PTSD in the context of rapidly evolving technologies that are constantly updating and adjusting our understanding of epigenetic modifications and their functional roles. Finally, we discuss the potential application of epigenetic approaches in identifying markers of risk and resilience that can be utilized to promote early intervention and develop therapeutic strategies to combat PTSD after symptom onset.
Ogryzko, Vasily V
Schroedinger's book 'What is Life?' is widely credited for having played a crucial role in development of molecular and cellular biology. My essay revisits the issues raised by this book from the modern perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of epigenetic stability: 'epigenetic templating' and 'systems biology' approaches, and consider them from the point of view expressed by Schroedinger. I also discuss how quantum entanglement, a nonclassical feature of quantum mechanics, can help to address the 'problem of small numbers' that led Schroedinger to promote the idea of a molecular code-script for explaining the stability of biological order.
Ogryzko Vasily V
Full Text Available Abstract Schroedinger's book 'What is Life?' is widely credited for having played a crucial role in development of molecular and cellular biology. My essay revisits the issues raised by this book from the modern perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of epigenetic stability: 'epigenetic templating' and 'systems biology' approaches, and consider them from the point of view expressed by Schroedinger. I also discuss how quantum entanglement, a nonclassical feature of quantum mechanics, can help to address the 'problem of small numbers' that led Schroedinger to promote the idea of a molecular code-script for explaining the stability of biological order.
In the past decades, studies on twins have had a great impact on dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable samples of twins help to bridge the gap between gene activity and environmental conditions...... through multiple epigenetic mechanisms. This paper reviews the new developments in using twins to study disease-related epigenetic alterations, links them to lifetime environmental exposure with a focus on the discordant twin design and proposes novel data-analytical approaches with the aim of promoting...... a more efficient use of twins in epigenetic studies of complex human diseases....
Talens, Rudolf P; Christensen, Kaare; Putter, Hein
The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk of most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18-89 years, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass......-related increase in methylation variation was generally attributable to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ...
Ryall, James G.; Cliff, Tim; Dalton, Stephen; Sartorelli, Vittorio
Summary For many years, stem cell metabolism was viewed as a by product of cell fate status rather than an active regulatory mechanism, however there is now a growing appreciation that metabolic pathways influence epigenetic changes associated with lineage commitment, specification, and self-renewal. Here we review how metabolites generated during glycolytic and oxidative processes are utilized in enzymatic reactions leading to epigenetic modifications and transcriptional regulation. We discuss how “metabolic reprogramming” contributes to global epigenetic changes in the context of naïve and primed pluripotent states, somatic reprogramming, and hematopoietic and skeletal muscle tissue stem cells, and the implications for regenerative medicine. PMID:26637942
Schroedinger's book 'What is Life?' is widely credited for having played a crucial role in development of molecular and cellular biology. My essay revisits the issues raised by this book from the modern perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of epigenetic stability: 'epigenetic templating' and 'systems biology' approaches, and consider them from the point of view expressed by Schroedinger. I also discuss how quantum entanglement, a nonclassical feature of quantum mechanics, can help to address the 'problem of small numbers' that lead Schroedinger to promote the idea of molecular code-script for explanation of stability of biological order.
Mirouze, Marie; Paszkowski, Jerzy
Plant epigenetics has recently gained unprecedented interest, not only as a subject of basic research but also as a possible new source of beneficial traits for plant breeding. We discuss here mechanisms of epigenetic regulation that should be considered when undertaking the latter. Since these mechanisms are responsible for the formation of heritable epigenetic gene variants (epialleles) and also regulate transposons mobility, both aspects could be exploited to broaden plant phenotypic and genetic variation, which could improve long-term plant adaptation to environmental challenges and, thus, increase productivity.
Kasuga, Takao; Gijzen, Mark
A feature of pathogenic and invasive organisms is their adaptability when confronted with host and environmental challenges. Recent studies have demonstrated that plant pathogens rely on epigenetic processes for this purpose. Epiallelic variation of effector genes that results in evasion of host immunity is one emerging phenomenon. Another is the epigenetically induced reprogramming and diversification of transcriptional patterns by de-repression of transposable elements. These observations indicate that epigenetic control of gene expression provides a versatile means of generating phenotypic diversity that is adaptable and heritable across generations.
Kawashima, Tomokazu; Berger, Frédéric
Epigenetic reprogramming consists of global changes in DNA methylation and histone modifications. In mammals, epigenetic reprogramming is primarily associated with sexual reproduction and occurs during both gametogenesis and early embryonic development. Such reprogramming is crucial not only to maintain genomic integrity through silencing transposable elements but also to reset the silenced status of imprinted genes. In plants, observations of stable transgenerational inheritance of epialleles have argued against reprogramming. However, emerging evidence supports that epigenetic reprogramming indeed occurs during sexual reproduction in plants and that it has a major role in maintaining genome integrity and a potential contribution to epiallelic variation.
LI Shijie; DU Weihua; LI Ning
Somatic cloning has been succeeded in some species, but the cloning efficiency is very low, which limits the application of the technique in many areas of research and biotechnology. The cloning of mammals by somatic cell nuclear transfer (NT) requires epigenetic reprogramming of the differentiated state of donor cell to a totipotent, embryonic ground state. Accumulating evidence indicates that incomplete or inappropriate epigenetic reprogramming of donor nuclei is likely to be the primary cause of failures in nuclear transfer. This review summarizes the roles of various epigenetic mechanisms, including DNA methylation, histone acetylation, imprinting, X-chromosome inactivation, telomere maintenance and expressions of development-related genes on somatic nuclear transfer.