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BBA - General Subjects (v.1790, #9)
Hunting for the 5th base: Techniques for analyzing DNA methylation by Ole Ammerpohl ⁎; José I. Martín-Subero; Julia Richter; Inga Vater; Reiner Siebert (pp. 847-862).
In the recent past large progress has been made in the analysis of the epigenome, the entirety of epigenetic modifications, and its meaning for the implementation of the genetic code. Besides histone modifications and miRNA expression, DNA methylation is one of the key players in the field of epigenetics, involved in numerous regulatory processes.In the present review we focus on methods for the analysis of DNA methylation patterns and present an overview about techniques and basic principles available for this purpose.We here discuss advantages and disadvantages of various methods and their feasibility for specific tasks of DNA methylation analysis.
Keywords: DNA methylation; Maxam–Gilbert; Bisulphite sequencing; Methylation sensitive restriction enzyme; Methylated DNA immunoprecipitation; MeDIP; MSP; LUMA
Histone modification patterns and epigenetic codes by Andreas Lennartsson; Karl Ekwall ⁎ (pp. 863-868).
The eukaryotic DNA is wrapped around histone octamers, which consist of four different histones, H2A, H2B, H3 and H4. The N-terminal tail of each histone is post-transcriptionally modified. The modification patterns constitute codes that regulate chromatin organisation and DNA utilization processes, including transcription. Recent progress in technology development has made it possible to perform systematic genome-wide studies of histone modifications. This helps immensely in deciphering the histone codes and their biological influence. In this review, we discuss the histone modification patterns found in genome-wide studies in different biological models and how they influence cell differentiation and carcinogenesis.
Keywords: Epigenetic; Chromatin; Histone code; Histone modification; Cell differentiation; Cancer
Epigenetic mechanisms in schizophrenia by Tania L. Roth; Farah D. Lubin; Monsheel Sodhi; Joel E. Kleinman (pp. 869-877).
Epidemiological research suggests that both an individual's genes and the environment underlie the pathophysiology of schizophrenia. Molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. Recent work indicates that epigenetic mechanisms, or the chemical markings of the DNA and the surrounding histone proteins, remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. In this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where ‘nature’ is considered to be inherited or genetic vulnerability to schizophrenia, and ‘nurture’ is proposed to exert its effects through epigenetic mechanisms. Second, we define DNA methylation and discuss the evidence for its role in schizophrenia. Third, we define posttranslational histone modifications and discuss their place in schizophrenia. This research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia.
Keywords: Schizophrenia; Environment; Epigenetic; DNA methylation; Histone; HDAC; DNMT; Cognition
The early life environment and the epigenome by Moshe Szyf (pp. 878-885).
Several lines of evidence point to the early origin of adult onset disease. A key question is: what are the mechanisms that mediate the effects of the early environment on our health? Another important question is: what is the impact of the environment during adulthood and how reversible are the effects of early life later in life? The genome is programmed by the epigenome, which is comprised of chromatin, a covalent modification of DNA by methylation and noncoding RNAs. The epigenome is sculpted during gestation, resulting in the diversity of gene expression programs in the distinct cell types of the organism. Recent data suggest that epigenetic programming of gene expression profiles is sensitive to the early-life environment and that both the chemical and social environment early in life could affect the manner by which the genome is programmed by the epigenome. We propose that epigenetic alterations early in life can have a life-long lasting impact on gene expression and thus on the phenotype, including susceptibility to disease. We will discuss data from animal models as well as recent data from human studies supporting the hypothesis that early life social-adversity leaves its marks on our epigenome and affects stress responsivity, health, and mental health later in life.
Keywords: Epigenetic; DNA methylation; Chromatin modification; Histone acetylation; DNA methyltransferase; Stress response; Early life experience
Epigenetics and atherosclerosis by Mikko P. Turunen; Einari Aavik; Seppo Ylä-Herttuala ⁎ (pp. 886-891).
The contribution of epigenetic mechanisms to cardiovascular diseases remains poorly understood. Hypomethylation of genomic DNA is present in human atherosclerotic lesions and methylation changes also occur at the promoter level of several genes involved in the pathogenesis of atherosclerosis, such as extracellular superoxide dismutase, estrogen receptor-α, endothelial nitric oxide synthase and 15-lipoxygenase. So far, no clear data is available about histone modification marks in atherosclerotic lesions. It remains unclear whether epigenetic changes are causally related to the pathogenetic features, such as clonal proliferation of lesion smooth muscle cells, lipid accumulation and modulation of immune responses in the lesions, or whether they merely represent a consequence of the ongoing pathological process. However, epigenetic changes could at least partly explain poorly understood environmental and dietary effects on atherogenesis and the rapid increases and decreases in the incidence of coronary heart disease observed in various populations. RNAi mechanisms may also contribute to the epigenetic regulation of vascular cells. Therapies directed towards modification of the epigenetic status of vascular cells might provide new tools to control atherosclerosis-related cardiovascular diseases.
Keywords: Atherosclerosis; Epigenetic; Hypercholesterolemia; Homocysteinemia; Methylation; Histone code
Epigenetics in hyperhomocysteinemic states. A special focus on uremia by Diego Ingrosso; Alessandra F. Perna (pp. 892-899).
Aim of this article is to review the topic of epigenetic control of gene expression, especially regarding DNA methylation, in chronic kidney disease and uremia. Hyperhomocysteinemia is considered an independent cardiovascular risk factor, although the most recent intervention studies utilizing folic acid are negative. The accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which is itself considered a predictor of cardiovascular events. The extent of methylation inhibition of each individual methyltransferase depends on the methyl donor S-adenosylmethionine (AdoMet) availability, on the [AdoMet]/[AdoHcy] ratio, and on the individual Km value for AdoMet and Ki for AdoHcy. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, almost unequivocally show. In vivo, DNA methylation may be also influenced by various factors in different tissues, for example by rate of cell growth, folate status, etc. and importantly inflammation.In chronic kidney disease and in uremia, hyperhomocysteinemia is commonly seen, and can be associated with global DNA hypomethylation, and with abnormal allelic expression of genes regulated through methylation. This alteration is susceptible of reversal upon homocysteine-lowering therapy obtained through folate administration. If this abnormality will translate itself in alterations of expression of genes relevant to the pathogenesis of this disease still remains to be established. In addition, these results establish a link between the epigenetic control of gene expression and xenobiotic influences, such as folate therapy.
Keywords: Uremia; Homocysteine; Epigenetics; DNA methylation; Cardiovascular risk
Epigenetic states in stem cells by Philippe Collas ⁎ (pp. 900-905).
Whereas embryonic stem cells can differentiate into all cell types of the body, stem cells found in somatic tissues display more restrictive differentiation capacity. The extent of multi-lineage differentiation ability of stem cells is believed to be associated with the potential for expression of developmentally- and differentiation-regulated genes. Growing evidence suggests that this potential for gene expression in undifferentiated cells is regulated by epigenetic processes on DNA and chromatin in regulatory and coding regions. Genome-wide mapping of DNA methylation profiles and of post-translational histone modifications in stem cells and differentiated cells has led to the establishment of chromatin states primarily on promoters of active, repressed and potentially active genes. These maps contribute to unveiling regulatory mechanisms by which genes are poised for transcription in undifferentiated cells. We summarize here the current view of how specific combinations of epigenetic marks may define the pluripotent state.
Keywords: Chromatin; DNA methylation; Embryonic stem cell; Epigenetic; Mesenchymal stem cell
At the crossroads of T helper lineage commitment—Epigenetics points the way by Peter C.J. Janson; Malin E. Winerdal; Ola Winqvist (pp. 906-919).
The immune system has the capacity to respond to various types of pathogens including bacteria, viruses, tumors and parasites. This requires a flexible immune system, which in part depends on the development of alternative effector T helper cells, with different cytokine repertoires that direct the overall immune response. The reciprocal effects of the T helper subtypes Th1 and Th2 are well documented, but the mechanisms involved in alternative cytokine expression and silencing are less well defined. Introduction of advances within the field of chromatin folding and epigenetic regulation of transcription has begun to explain some of the fundamental principles of T helper cell development. In addition, epigenetic regulation has proven essential also for the more recently discovered T helper cell subtypes; regulatory T cells and the Th17 lineage. As the importance of proper epigenetic regulation becomes evident, attention is also focused on the potential harmfulness of epigenetic dysregulation. Autoimmunity and allergy are two clinical situations that have been implicated as results of imperfect cytokine silencing. This review will address recent advances in the field of epigenetic regulation of T lymphocytes and their maturation from naive cells into different effector T cell lineages. In particular, epigenetic involvement in regulation of key effector cytokines and specific transcription factors determining the CD4+ T lymphocyte lineage commitment will be discussed.
Keywords: Epigenetics; CD4 positive T lymphocyte; Regulatory T lymphocyte; Th1 cell; Th2 cell; Th17 cell
Seed in soil, with an epigenetic view by Huey-Jen L. Lin ⁎; Tao Zuo; Jennifer R. Chao; Zhengang Peng; Lisa K. Asamoto; Sonya S. Yamashita; Tim H.-M. Huang ⁎ (pp. 920-924).
It is becoming increasingly evident that discrete genetic alterations in neoplastic cells alone cannot explain multistep carcinogenesis whereby tumor cells are able to express diverse phenotypes during the complex phases of tumor development and progression. The epigenetic model posits that the host microenvironment exerts an initial, inhibitory constraint on tumor growth that is followed by acceleration of tumor progression through complex cell–matrix interactions. This review emphasizes the epigenetic aspects of breast cancer development in light of such interactions between epithelial cells (“seed”) and the tumor microenvironment (“soil”). Our recent research findings suggest that epigenetic perturbations induced by the tumor microenvironment may play a causal role in promoting breast cancer development. It is believed that abrogation of these initiators could offer a promising therapeutic strategy.
Keywords: Breast cancer; Tumor microenvironment; Stromal fibroblast; Epigenetics; DNA methylation; Chromatin remodeling
Contributions of extracellular matrix signaling and tissue architecture to nuclear mechanisms and spatial organization of gene expression control by Sophie A. Lelièvre (pp. 925-935).
Post-translational modification of histones, ATP-dependent chromatin remodeling, and DNA methylation are interconnected nuclear mechanisms that ultimately lead to the changes in chromatin structure necessary to carry out epigenetic gene expression control. Tissue differentiation is characterized by a specific gene expression profile in association with the acquisition of a defined tissue architecture and function. Elements critical for tissue differentiation, like extracellular stimuli, adhesion and cell shape properties, and transcription factors all contribute to the modulation of gene expression and thus, are likely to impinge on the nuclear mechanisms of epigenetic gene expression control. In this review, we analyze how these elements modify chromatin structure in a hierarchical manner by acting on the nuclear machinery. We discuss how mechanotransduction via the structural continuum of the cell and biochemical signaling to the cell nucleus integrate to provide a comprehensive control of gene expression. The role of nuclear organization in this control is highlighted, with a presentation of differentiation-induced nuclear structure and the concept of nuclear organization as a modulator of the response to incoming signals.
Keywords: Abbreviations; 3D; three-dimensional; CRC; chromatin remodeling complex; ECM; extracellular matrix; ERE; ECM responsive element; HAT; histone acetylase; HDAC; histone deacetylase; HP1; heterochromatin protein 1; SRF; serum response factor; TSA; trichostatin AChromatin; Histone; ATP-dependent chromatin remodeling; Cell shape; Differentiation; Nuclear organization
Regulation of the mammalian epigenome by long noncoding RNAs by Joanne Whitehead; Gaurav Kumar Pandey; Chandrasekhar Kanduri (pp. 936-947).
Genomic analyses have demonstrated that although less than 2% of the mammalian genome encodes proteins, at least two thirds is transcribed. Many nontranslated RNAs have now been characterized, and several long transcripts, ranging from 0.5 to over 100 kb, have been shown to regulate gene expression by modifying chromatin structure. Functions uncovered at a few well characterized loci demonstrate a wide diversity of mechanisms by which long noncoding RNAs can regulate chromatin over a single promoter, a gene cluster, or an entire chromosome, in order to activate or silence genes in cis or in trans. In reviewing the activities of these ncRNAs, we will look for common features in their interactions with the chromatin modifying machinery, and highlight new experimental approaches by which to address outstanding issues in ncRNA-dependent regulation of gene expression in development, disease and evolution.
Keywords: Noncoding RNA; Chromatin; Epigenetic; Antisense RNA; Gene regulation