Role Of Epigenetic Mechanisms Research Articles

Promoter Methylation Status Modulate the Expression of Tumor Suppressor (RbL2/p130) Gene in Breast Cancer.

BackgroundAberrant expression of tumor suppressor genes may correspond to the abnormal cell development and tumorigenesis. Rbl2/p130, a member of retinoblastoma family of proteins, has growth suppressive properties. Numerous studies reported de-regulation of Rbl2/p130 in various types of cancer as a consequence of a number of genetic alterations. However, role of epigenetic mechanisms like DNA methylation in Rbl2/p130 expression remains elusive.MethodsIn the current study, 76 breast cancer tumors along with normal tissues (n = 76), blood (n = 76) of respective individuals and control blood (n = 50) were analyzed. Rbl2/p130 expression was analyzed by quantitative real time PCR (syber green method). Promoter methylation status was studied through methylation specific PCR of bisulfite converted genomic DNA. Data was analyzed using various statistical tests.ResultsWe report significantly reduced Rbl2/p130 expression (P = 0.001) in tumors tissues as compared to control samples. Similarly, Rbl2/p130 expression varies with age and disease stages (P = 0.022), which suggest its involvement in tumor progression. Aberrant promoter methylation (Δmeth) was found in almost all the diseased samples and that was significantly different (P<0.001) with control samples. Similarly, methylation status varies significantly with tumor progression stages (P = 0.022). Hyper-methylation was observed at -1, +3, +15 and +75 of Rbl2/p130 promoter flanking around the TSS. Statistical analysis revealed that Rbl2/p130 expression negatively correlates to its promoter methylation (r = -0.412) in tumor tissues. Our results reflect an epigenetic regulation of Rbl2/p130 expression in breast cancer. This highlights the importance of Rbl2/p130 promoter methylation in breast cancer pathogenesis.

Expansion of the polycomb system and evolution of complexity

Polycomb group (PcG) proteins regulate and maintain expression pattern of genes set early during development. Although originally isolated as regulators of homeotic genes, PcG members play a key role in epigenetic mechanisms that maintain the expression state of a large number of genes. All members of the two polycomb repressive complexes (PRC1 and PRC2) are conserved during evolution and while invertebrates generally have one gene for each of these, vertebrates have multiple homologues of them. It remains unclear, however, if different vertebrate PcG homologues have distinct or overlapping functions. We have identified and compared the sequence of PcG homologues in various organisms to analyze similarities and differences that shaped the evolutionary history of these proteins. Comparative analysis of the sequences led to the identification of several novel and signature motifs in the vertebrate homologues of these proteins, which can be directly used to pick respective homologues. Our analysis shows that PcG is an ancient gene group dating back to pre-bilaterian origin that has not only been conserved but also expanded during the evolution of complexity. The presence of unique motifs in each paralogue and its conservation for more than 500Ma indicates their functional relevance and probable unique role. Although this does not rule out completely any overlapping function, our finding that these homologues only minimally overlap in their nuclear localization suggests that each PcG homologue has distinct function. We further propose distinct complex formation by the PcG members. Taken together, our studies suggest non-redundant and specific role of multiple homologues of PcG proteins in vertebrates and indicate major expansion event preceded by emergence of vertebrates that contributed as enhanced epigenetic resource to the evolution of complexity.

Abstract 818: Chronic oxidative stress induces conversion of estrogen-dependent non-aggressive breast cancer cells into estrogen-independent aggressive phenotype

Abstract We have recently reported increased growth and tumorigenic potential of estrogen receptor (ER) positive breast cancer cells with chronic exposure to oxidative stress. In this study, we evaluated mechanistic basis for chronic oxidative stress-induced aggressiveness in ER positive MCF-7 breast cancer cells. Loss of estrogen dependency is known to be associated with acquisition of aggressive form in breast cancer cells. Therefore, the objective of this study was to evaluate changes in estrogen response in ER-positive breast cancer cells exposed to chronic oxidative stress. MCF-7 cells were exposed to hydrogen peroxide (H2O2)-induced oxidative stress for chronic period (6 months). Using these cells, growth response to 17-β estradiol was evaluated by MTT assay and cell cycle analysis. Surprisingly, in response to 17-β estradiol treatment, there was no significant growth stimulation in cells exposed to chronic oxidative stress. Cell cycle analysis by flow cytometry further confirmed the cell growth data. Quantitative RT-PCR analysis also revealed significant down regulation of ER-α in chronically exposed breast cancer cells. To understand the role of epigenetic mechanism, the expression of epigenetic regulatory genes were determined at both transcript and protein level. In addition, the levels of histone modifications were also evaluated by Western blot analysis. Changes in both the expression of epigenetic regulatory genes (DNMT1, DNMT3b, HDAC1, MBD4, and HAT1) and the levels of histone modifications (H3K27 tri-methylation and H3K18 acetylation) were observed in MCF-7 cells chronically exposed to H2O2. Treatment with DNA de-methylating agent (5-aza-2′-deoxycytidine) restored the ER-α expression level, estrogen-induced growth and oxidative stress induced histone modifications. To summarize, the findings of this study suggest that chronic exposure to oxidative stress can convert estrogen-dependent non-aggressive breast cancer cells into estrogen-independent aggressive form potentially by epigenetic mechanism. Citation Format: Prathap Kumar S. Mahalingaiah, Logeswari Ponnusamy, Kamaleshwar P. Singh. Chronic oxidative stress induces conversion of estrogen-dependent non-aggressive breast cancer cells into estrogen-independent aggressive phenotype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 818. doi:10.1158/1538-7445.AM2015-818

Expanding fundamental ecological knowledge by studying urban ecosystems

The expansion, densification and proliferation of urban areas around the world is currently occurring at a rate that is unprecedented in human history. It is predicted that global urban land cover will triple between 2000 and 2030, with some regions (including biodiversity hotspots) experiencing a ninefold increase in urban land cover over the same time period (Seto, G€ uneralp & Hutyra 2012). Accompanying the expansion of urban landscapes, it is anticipated that the human population living in cities and towns globally will increase from 3 5 to 5 billion people within the next 20 years (Fragkias et al. 2013). Thus, the demands of an expanding and urbanizing human population are one of the pressing ecological problems our world is facing (Sanderson et al. 2002), alongside, and in combination with, global climate change and changes to biodiversity at local and global scales (Pimm et al. 2014). Yet, urban environments also present a unique opportunity to expand our fundamental knowledge related to ecology and evolution due to the presence of intense and often novel selection pressures. In the inaugural issue of this journal, Calow (1987) defined functional ecology as the sum of three interactive processes: (i) those occurring between organisms and their environment, (ii) biotic interactions between organisms and (iii) adaptive processes driven by natural selection. The same three processes were highlighted 1 year earlier by Jared Diamond in Nature, when he called for biologists to pay more attention to the potential of using the unprecedented environmental conditions that exist within towns and cities to develop and test evolutionary and ecological theory (Diamond 1986). There is thus a natural synergy between functional ecology and urban ecology, as exemplified by some of the classic papers that have appeared in this journal, such as Rydell (1992) who demonstrated that the form of echolocation system determined the impact of light pollution on bat foraging behaviour. The potential of combining functional ecological research with urban ecology is, however, a long way from being fully realized. This is in part explained by the youth of urban ecology as a discipline. Scientific enquiry into the ecological consequences of urban environments has been underway for over half a century, although most of the momentum emerged after the mid 1990s (McDonnell 2011; Wu 2014). Thus, the focus of much urban research to date has involved describing patterns along environmental gradients (Gagn e 2013; McDonnell & Hahs 2013) rather than investigating the mechanistic processes that lie at the heart of functional ecology. To be effective in addressing the global challenges of urbanization, a much better understanding of how the urban environment affects the ecology and evolution of organisms needs to be developed (Grimm et al. 2008; Marzluff 2012; Gil & Brumm 2014; McDonnell & Hahs 2015). The purpose of this special feature is to draw attention to the plethora of opportunities that await researchers investigating the ecology and evolution of organisms in urban environments. The combination of environmental stressors and conditions within urban areas provides a novel opportunity to test and expand our theories related to ecology and evolution of organisms, and some intriguing insights are already beginning to emerge. For example, the detailed understanding of the molecular, genetic and developmental mechanisms of beak evolution that has arisen from studying Galapagos finches has been significantly advanced by studying beak evolution in the house finch Carpodacus mexicanus in response to novel urban food sources and its consequences for acoustic communication (Badyaev 2010, 2014). Thus, urban ecology has the potential to extend our understanding of extremely well-studied ecological and evolutionary problems.

Epigenetic Modulation of Intestinal NHE3 Expression by DNA Methylation

NHE3 plays an important role in intestinal Na+ absorption and its down-regulation has been implicated in inflammatory diarrhea. Recent evidence also indicates a novel role of epigenetic mechanisms, such as DNA methylation in the pathophysiology of IBD. Whether changes in DNA methylation are involved in modulating intestinal NHE3 gene expression is not known. To address this, methyl-CpG binding domain-based capture assay was performed in Caco2 cells treated with the pro-inflammatory cytokines. IL6 (100 ng/ml) or IL1β (50 ng/ml) for 48h increased DNA methylation at the NHE3 gene promoter, indicating that DNA methylation may contribute to the decrease in NHE3 expression during intestinal inflammation. In parallel, in vitro methylation of NHE3 promoter (p-1507/+131) cloned into a CpG free lucia vector decreased the promoter activity. Conversely, DNA methyltransferase (DNMT) inhibitor, 5-azacytidine (10 μM, 24h) caused a significant decrease in DNA methylation of NHE3 gene. Also, 5-aza increased NHE3 expression in Caco2 & duodenal HUTU-80 cells by ~2-3 fold (p<0.05). Treatment of mice with 5-aza for 3 wks resulted in an increase in NHE3 expression in the ileum and colon (~2 fold, p<0.05). Further, the role of the demethylase GADD45β was examined. siRNA knockdown of GADD45β in Caco2 cells decreased NHE3 mRNA expression by ~50% (p<0.05). Immunostaining showed a decrease in NHE3 expression in the ileum & colon of GADD45β -/- mice. These findings suggest that changes in DNA methylation may be involved in the inhibition of NHE3 gene expression in intestinal inflammation contributing to the pathophysiology of IBD-associated diarrhea. (Supported by VA/NIH)

Epigenetic mechanisms in neurological and neurodegenerative diseases.

The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS) and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS’s regulation and neurological disorders are mediated via modulation of chromatin structure. “Epigenetics”, introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA), nicotinamide adenine dinucleotide (NAD+) and beta hydroxybutyrate (β-HB), regulates some of these epigenetic modifications, linking in a precise way environment with gene expression. This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of epigenetics and neurological disorders.

The role of epigenetic mechanisms in Notch signaling during development.

The Notch pathway is a highly conserved cell-cell communication pathway in metazoan involved in numerous processes during embryogenesis, development, and adult organisms. Ligand-receptor interaction of Notch components on adjacent cells facilitates controlled sequential proteolytic cleavage resulting in the nuclear translocation of the intracellular domain of Notch (NICD). There it binds to the Notch effector protein RBP-J, displaces a corepressor complex and enables the induction of target genes by recruitment of coactivators in a cell-context dependent manner. Both, the gene-specific repression and the context dependent activation require an intense communication with the underlying chromatin of the regulatory regions. Since the epigenetic landscape determines the function of the genome, processes like cell fate decision, differentiation, and self-renewal depend on chromatin structure and its remodeling during development. In this review, structural features enabling the Notch pathway to read these epigenetic marks by proteins interacting with RBP-J/Notch will be discussed. Furthermore, mechanisms of the Notch pathway to write and erase chromatin marks like histone acetylation and methylation are depicted as well as ATP-dependent chromatin remodeling during the activation of target genes. An additional fine-tuning of transcriptional regulation upon Notch activation seems to be controlled by the commitment of miRNAs. Since cells within an organism have to react to environmental changes, and developmental and differentiation cues in a proper manner, different signaling pathways have to crosstalk to each other. The chromatin status may represent one major platform to integrate these different pathways including the canonical Notch signaling.

The Role of Epigenetic Mechanisms in Substance Use Disorders: An Overview

“Substance use disorder” (SUD) is a common, chronic, remitting/relapsing group of psychiatric disorders having devastating effect not only on the individual but also impose socio-economic burden on their families and the society at large. They are often accompanied with numerous maladaptive behaviors and a persistent and compulsive, uncontrolled use of substance. Interestingly, they have moderate to high heritability and seem to be modulated by both genes and environment. Recent researches suggest that interactions of environmental and genetic factors designate the significance of epigenetic mechanisms, which have been found to occur in SUDs. This review makes an attempt to provide an overview regarding the various types of epigenetic modifications and their application in relation to SUDs.

Epigenetic analysis of sporadic and Lynch-associated ovarian cancers reveals histology-specific patterns of DNA methylation

Diagnosis and treatment of epithelial ovarian cancer is challenging due to the poor understanding of the pathogenesis of the disease. Our aim was to investigate epigenetic mechanisms in ovarian tumorigenesis and, especially, whether tumors with different histological subtypes or hereditary background (Lynch syndrome) exhibit differential susceptibility to epigenetic inactivation of growth regulatory genes. Gene candidates for epigenetic regulation were identified from the literature and by expression profiling of ovarian and endometrial cancer cell lines treated with demethylating agents. Thirteen genes were chosen for methylation-specific multiplex ligation-dependent probe amplification assays on 104 (85 sporadic and 19 Lynch syndrome-associated) ovarian carcinomas. Increased methylation (i.e., hypermethylation) of variable degree was characteristic of ovarian carcinomas relative to the corresponding normal tissues, and hypermethylation was consistently more prominent in non-serous than serous tumors for individual genes and gene sets investigated. Lynch syndrome-associated clear cell carcinomas showed the highest frequencies of hypermethylation. Among endometrioid ovarian carcinomas, lower levels of promoter methylation of RSK4, SPARC, and HOXA9 were significantly associated with higher tumor grade; thus, the methylation patterns showed a shift to the direction of high-grade serous tumors. In conclusion, we provide evidence of a frequent epigenetic inactivation of RSK4, SPARC, PROM1, HOXA10, HOXA9, WT1-AS, SFRP2, SFRP5, OPCML, and MIR34B in the development of non-serous ovarian carcinomas of Lynch and sporadic origin, as compared to serous tumors. Our findings shed light on the role of epigenetic mechanisms in ovarian tumorigenesis and identify potential targets for translational applications.

Analysis of the bone microRNome in osteoporotic fractures.

Osteoporosis causes important morbidity among elderly individuals. Fragility fractures, and especially hip fractures, have a particularly negative impact on the patients' quality of life. The role of epigenetic mechanisms in the pathogenesis of many disorders is increasingly recognized, yet little is known about their role in non-malignant bone disorders such as osteoporosis. The aim of this study was to explore the expression of miRNAs in patients with osteoporotic hip fractures. Trabecular bone samples were obtained from the femoral heads of patients undergoing replacement surgery for osteoporotic hip fractures and non-fracture controls with hip osteoarthritis. Levels of 760 miRNA were analyzed by real-time PCR. Thirteen miRNAs showed nominally significant (p<0.05) differences between both groups. Six miRNAs (miR-187, miR-193a-3p, miR-214, miR518f, miR-636, and miR-210) were selected for the replication stage. These miRNAs were individually analyzed in a larger group of 38 bone samples. At this stage, we confirmed statistically significant differences across groups for mir-187 and miR-518f. The median relative expression levels of miR-187 were 5.3-fold higher in the non-fracture group (p=0.002). On the contrary, miR-518f was preferentially expressed in bones from osteoporotic patients (8.6-fold higher in fractures; p=0.046). In this first hypothesis-free study of the bone microRNome we found two miRNAs, miR-187, and miR-518f, differentially regulated in osteoporotic bone. Further studies are needed to elucidate the mechanisms involved in the association of these miRNAs with fractures.

Epigenetic programming by early-life stress: Evidence from human populations.

A substantial body of experimental and epidemiological evidence has been accumulated suggesting that stressful events in early life including acute perinatal stress, maternal deprivation or separation, and variation in maternal care may lead to neuroendocrine perturbations thereby affecting reproductive performance, cognitive functions, and stress responses as well as the risk for infectious, cardio-metabolic and psychiatric diseases in later life. Findings from recent studies based on both genome-wide and candidate gene approaches highlighted the importance of mechanisms that are involved in epigenetic regulation of gene expression, such as DNA methylation, histone modifications, and non-coding RNAs, in the long-term effects of exposure to stress in early life. This review is focused on the findings from human studies indicating the role of epigenetic mechanisms in the causal link between early-life stress and later-life health outcomes.

The role of DNA methylation: a challenge for the DOHaD paradigm in going beyond the historical debate.

A heritage of considerable research into such phenomena as parental imprinting and carcinogenesis is an almost axiomatic association of the DNA methylation epigenetic mark with the silencing of gene expression. However, the increasing technical resolution afforded by burgeoning -omics technologies reveals that a more elaborate interaction may exist between DNA methylation, within sub-regions of gene structure and/or specific dinucleotide sites, and levels of gene activity. Furthermore, seminal observations from the field of DOHaD, which clearly define the alignment of sequential epigenetic modifications and gene activity appear not to support a strictly causal relationship between DNA methylation and gene silencing. The temporal element implicit within DOHaD studies provides a useful framework within which to further explore the role of epigenetic mechanisms and in particular perhaps, to address the question of 'deterministic intent' when implicating the epigenetic regulation of gene activity in the manifestation of phenotype.

Abstract 496: Adaptive response to chronic oxidative stress involves epithelial-mesenchymal transition in MCF-7 breast cancer cells

Abstract Though the increased oxidative stress by endogenous and exogenous factors has been hypothesized as a potential mechanism for breast cancer growth and progression, but there is no direct mechanistic evidence for adaptation to ROS-induced toxicity by the breast cancer cells. Therefore the objective of this study was to evaluate effects of chronic oxidative stress on the growth, survival and tumorigenicity of MCF-7 breast cancer cells. MCF-7 cells were exposed to hydrogen peroxide (H202) induced oxidative stress for both acute (48 hrs) and chronic (3 months) period. Cell growth and viability were evaluated by cell count and MTT assay and were confirmed by cell cycle analysis. Expression of genes related to cell cycle, cell survival, and metastasis were measured by quantitative real-time PCR. Effect of oxidative stress on tumorigenic phenotype was determined in-vitro by soft agar assay. Results of cell count, MTT and cell cycle analysis revealed increased growth, and survival of MCF-7 cells that was chronically exposed to H2O2. This was further confirmed at molecular level by increased expression of cell cycle and cell survival genes, whereas down-regulation of apoptotic genes. Chronic oxidative stress also increased tumorigenic phenotype and metastatic potential of MCF-7 cells as revealed by increase in soft agar grown colonies and expression of metastasis related genes. Additionally, fibroblast-like appearance with down regulation of epithelial markers, whereas up-regulation of mesenchymal markers in cells with chronic exposure to oxidative stress further suggest that adaptation to chronic oxidative stress by MCF-7 cells involves epithelial to mesenchymal transition (EMT). Dysregulation of epigenetic regulatory genes expression also suggest potential role of epigenetic mechanism in increased survival and tumorigencity of breast cancer cells.The findings of this study for the first time provided direct evidence for involvement EMT and epigenetic changes in adaptation of MCF-7 breast cancer cells to chronic oxidative stress. Results of this study are also highly significant in understanding the mechanism for acquired resistance to chemotherapeutic drugs that are known to produce ROS in breast cancer cells. Citation Format: Prathap Kumar S. Mahalingaiah, Logeswari Ponnusamy, Kamaleshwar P. Singh. Adaptive response to chronic oxidative stress involves epithelial-mesenchymal transition in MCF-7 breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2014-496

Temperature influences histone methylation and mRNA expression of the Jmj-C histone-demethylase orthologues during the early development of the oyster Crassostrea gigas

In many groups, epigenetic mechanisms influence developmental gene regulation under environmental inputs. The Pacific oyster Crassostrea gigas belongs to lophotrochozoans and its larval development is highly dependent on temperature, but the role of epigenetic mechanisms in this context is unknown despite high levels of the recently characterized Jumonji histone demethylase (JHDM) orthologues (Cg_Jumonji) suggesting a physiological relevance of histone methylation in the oyster development. Because in other species alterations of the histone methylation pattern have deleterious outcomes, we investigated the influence of temperature during the oyster larval life on histone methylation and JHDM expression. To shed light on this point, oyster embryonic and early larval development experiments were carried out at different temperatures (18°C, 25°C and 32°C). Histone methylation levels were investigated using fluorescent ELISA at 6 and 24h post-fertilization. When compared to the 25°C group, at 18°C H3K4, H3K9 and H3K27 residues were hypomethylated at 6h post fertilization (hpf) and hypermethylated at 24hpf. In contrast, at 32°C, 6hpf animals present a dramatic hypermethylation (ca. 4-fold) of all examined residues, which is minored but sustained at 24hpf. RT-qPCR investigations of the mRNA expression of the nine oyster JHDMs, showed gene- and stage-specific temperature sensitivities throughout the early life of oysters. This study provides evidence of the biological significance of histone methylation during development in a lophotrochozoan species. Our results also indicate that temperature influences histone methylation, possibly through the expression level of putative actors of its regulation, which might participate in developmental control. To our knowledge, this is the first report indicating a direct relationship between an epigenetic mark and an environmental parameter in marine molluscs. Such investigations could help better understand the molecular mechanisms of development and adaptation in lophotrochozoans.

Epigenetic control of gene function in schistosomes: a source of therapeutic targets?

The discovery of the epigenetic regulation of gene expression has revolutionized both our understanding of how genomes function and approaches to the therapy of numerous pathologies. Schistosomes are metazoan parasites and as such utilize most, if not all the epigenetic mechanisms in play in their vertebrate hosts: histone variants, histone tail modifications, non-coding RNA and, perhaps, DNA methylation. Moreover, we are acquiring an increasing understanding of the ways in which these mechanisms come into play during the complex schistosome developmental program. In turn, interest in the actors involved in epigenetic mechanisms, particularly the enzymes that carry out epigenetic modifications of histones or nucleic acid, as therapeutic targets has been stimulated by the finding that their inhibitors exert profound effects, not only on survival, but also on the reproductive function of Schistosoma mansoni. Here, we review our current knowledge, and what we can infer, about the role of epigenetic mechanisms in schistosome development, differentiation and survival. We will consider which epigenetic actors can be targeted for drug discovery and what strategies can be employed to develop potent, selective inhibitors as drugs to cure schistosomiasis.

Novel mechanistic insights into treadmill exercise based rescue of social defeat-induced anxiety-like behavior and memory impairment in rats

Social defeat (SD) induced stress causes physiological and behavioral deficits in rodents, including depression and anxiety-like behaviors, as well as memory impairment. Anxiolytic and mood elevating effects of physical exercise are also known. However, rescue effect of physical exercise in social defeat-induced anxiety, depression or memory impairment has not been addressed. The role of epigenetic mechanisms that potentially contribute to these rescue or protective effects is also not known. The present study investigated the effect of moderate treadmill exercise on anxiety-like behavior and memory function in rats subjected to SD using a modified version of the resident–intruder model for social stress (defeat). Changes in histone acetylation and histone-modifying enzymes were examined in hippocampus, amygdala and frontal cortex which are considered critical for anxiety, depression and cognition. Sprague Dawley rats were randomly assigned in four groups; control, exercised, social defeat, social defeat and exercise. At the end of the SD or control exposure lasting 30min daily for 7days, one group of SD rats was subjected to treadmill exercise for 2weeks, whereas the other SD group was handled without exercise. Anxiety-like behavior tests and radial arm water maze test suggested that moderate treadmill exercise rescued social defeat induced anxiety-like behavior and memory impairment. Moreover, exercise normalized SD-induced increase in oxidative stress, most likely by adjusting antioxidant response. Our data suggests involvement of epigenetic mechanisms including histone acetylation of H3 and modulation of methyl-CpG-binding in the hippocampus that might contribute to the rescue effects of exercise in SD-induced behavioral deficits in rats.

Epigenetics in health and disease: heralding the EWAS era

Epigenetics in health and disease: heralding the EWAS era

Epigenetic mechanisms in the pathogenesis of Lynch syndrome

Inherited defects in the DNA mismatch repair (MMR) system, MLH1, MSH2, MSH6, and PMS2 genes, underlie Lynch syndrome, one of the most prevalent cancer syndromes in man. The syndrome offers a model for cancers arising through MMR defects and microsatellite instability, which applies to ~ 15% of all colorectal, endometrial, and other cancers. Lynch syndrome also illustrates the significance of the epigenetic component in cancer development. Inactivation of tumor suppressor genes by epigenetic mechanisms is an acquired property of many tumors developing in Lynch syndrome. Furthermore, constitutional epimutations of MMR genes may explain a proportion of mutation-negative families lacking MLH1 or MSH2 protein expression in tumor tissue. This review provides an update of the molecular basis of Lynch syndrome by focusing on the role of epigenetic mechanisms in the pathogenesis of the disease.

Epigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes

Adaptation to environmental changes is based on the perpetual generation of new phenotypes. Modern biology has focused on the role of epigenetic mechanisms in facilitating the adaptation of organisms to changing environments through alterations in gene expression. Inherited and/or acquired epigenetic factors are relatively stable and have regulatory roles in numerous genomic activities that translate into phenotypic outcomes. Evidence that dietary and pharmacological interventions have the potential to reverse environment-induced modification of epigenetic states (e.g., early life experience, nutrition, medication, infection etc.) has provided an additional stimulus for understanding the biological basis of individual differences in cognitive abilities and disorders of the brain. It has been suggested that the accurate quantification of the relative contribution of heritable genetic and epigenetic variation is essential for understanding phenotypic divergence and adaptation in changing environments, a process requiring stable modulation of gene expression. The main challenge for epigenetics in psychology and psychiatry is to determine how experiences and environmental cues influence the expression of neuronal genes to produce long-term individual differences in behavior, cognition, personality and mental health. To this end, focusing on DNA and histone modifications and their initiators, mediators and readers may provide new inroads for understanding the molecular basis phenotypic plasticity and disorders of the brain. In this review, we survey recent developments revealing epigenetic aspects of mental illness, as well as review some of the challenges of current approaches and some future directions in the field of behavioral epigenetics.

Role of IL-6/JAK/STAT pathway in inducing vascular insulin resistance

Insulin resistance is a hall mark of metabolic disorders. Studies have demonstrated that inflammatory regulator interleukin-6 (IL-6) plays an important role in disruption of IR/Akt/eNOS signaling pathway resulting vascular insulin resistance. Accumulating evidences suggests a significant role of epigenetic mechanisms such as DNA methylation in progression of metabolic disorders. Hence the present study aimed to understand the role of epigenetic mechanisms involved during IL-6 induced vascular insulin resistance and its consequences in cardiovascular diseases.