Epigenetics: Connecting Environment and Genotype to Phenotype and Disease

Center for Oral and Systemic Diseases, Department of Periodontology, School of Dentistry, University of North Carolina at Chapel Hill, Room 222, CB 7455, Chapel Hill, NC 27599, USA.
Journal of dental research (Impact Factor: 4.14). 06/2009; 88(5):400-8. DOI: 10.1177/0022034509335868
Source: PubMed


Genetic information is encoded not only by the linear sequence of DNA, but also by epigenetic modifications of chromatin structure that include DNA methylation and covalent modifications of the proteins that bind DNA. These "epigenetic marks" alter the structure of chromatin to influence gene expression. Methylation occurs naturally on cytosine bases at CpG sequences and is involved in controlling the correct expression of genes. DNA methylation is usually associated with triggering histone deacetylation, chromatin condensation, and gene silencing. Differentially methylated cytosines give rise to distinct patterns specific for each tissue type and disease state. Such methylation-variable positions (MVPs) are not uniformly distributed throughout our genome, but are concentrated among genes that regulate transcription, growth, metabolism, differentiation, and oncogenesis. Alterations in MVP methylation status create epigenetic patterns that appear to regulate gene expression profiles during cell differentiation, growth, and development, as well as in cancer. Environmental stressors including toxins, as well as microbial and viral exposures, can change epigenetic patterns and thereby effect changes in gene activation and cell phenotype. Since DNA methylation is often retained following cell division, altered MVP patterns in tissues can accumulate over time and can lead to persistent alterations in steady-state cellular metabolism, responses to stimuli, or the retention of an abnormal phenotype, reflecting a molecular consequence of gene-environment interaction. Hence, DNA epigenetics constitutes the main and previously missing link among genetics, disease, and the environment. The challenge in oral biology will be to understand the mechanisms that modify MVPs in oral tissues and to identify those epigenetic patterns that modify disease pathogenesis or responses to therapy.

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Available from: Steven Offenbacher, Oct 08, 2015
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    • "The epigenome consists of chemical agents that modify, or mark, the genome, but are separate from the DNA itself. Effects of epigenetics are principally achieved by DNA and histone modifications that enhance or suppress gene expression (Barros and Offenbacher 2009). Epigenome-wide association studies are done to determine whether differences in histone and/or DNA modifications are associated with a trait (Michels et al. 2013). "
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked human disorder in which absence of the protein dystrophin causes degeneration of skeletal and cardiac muscle. For the sake of treatment development, over and above definitive genetic and cell-based therapies, there is considerable interest in drugs that target downstream disease mechanisms. Drug candidates have typically been chosen based on the nature of pathologic lesions and presumed underlying mechanisms and then tested in animal models. Mammalian dystrophinopathies have been characterized in mice (mdx mouse) and dogs (golden retriever muscular dystrophy [GRMD]). Despite promising results in the mdx mouse, some therapies have not shown efficacy in DMD. Although the GRMD model offers a higher hurdle for translation, dogs have primarily been used to test genetic and cellular therapies where there is greater risk. Failed translation of animal studies to DMD raises questions about the propriety of methods and models used to identify drug targets and test efficacy of pharmacologic intervention. The mdx mouse and GRMD dog are genetically homologous to DMD but not necessarily analogous. Subcellular species differences are undoubtedly magnified at the whole-body level in clinical trials. This problem is compounded by disparate cultures in clinical trials and preclinical studies, pointing to a need for greater rigor and transparency in animal experiments. Molecular assays such as mRNA arrays and genome-wide association studies allow identification of genetic drug targets more closely tied to disease pathogenesis. Genes in which polymorphisms have been directly linked to DMD disease progression, as with osteopontin, are particularly attractive targets.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 06/2014; 55(1):119-49. DOI:10.1093/ilar/ilu011 · 2.39 Impact Factor
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    • "In recent years, there has been increased recognition of the importance of the epigenome in maintaining cellular homeostasis, and therefore it has been hypothesized that environmentally-induced epigenetic perturbations may play an important role in disease development. Detailed descriptions of the various components of the epigenome are outside the scope and purpose of this work but are the subjects of reviews elsewhere [8, 9]. Briefly, the epigenome refers to potentially heritable biological information contained outside the DNA sequence that functions as regulators of gene function [8–10]. "
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    ABSTRACT: Inorganic arsenic (iAs) poses a major threat to worldwide human health, and yet the molecular mecha-nisms underlying the toxic effects associated with iAs ex-posure are not well understood. There is increasing exper-imental evidence indicating that epigenetic modifications may play a major role in the development of diseases associated with exposure to environmental toxicants. Re-search in the field has firmly established that iAs exposure is associated with epigenetic alterations including changes in DNA methylation, miRNA abundance, and post-translational histone modifications. Here, we summarize recent studies that have expanded the current knowledge of these relationships. These studies have pinpointed spe-cific regions of the genome and genes that are targets of arsenical-induced epigenetic changes, including those as-sociated with in utero iAs exposure. The recent literature indicates that iAs biotransformation likely plays an impor-tant role in the relationship between iAs exposure and the epigenome, in addition to the sex and genetic background of individuals. The research also shows that relatively low to moderate exposure to iAs is associated with epigenetic effects. However, while it is well established that arsenicals can alter components of the epigenome, in many cases, the biological significance of these alterations remains un-known. The manner by which these and future studies may help inform the role of epigenetic modifications in the development of iAs-associated disease is evaluated and the need for functional validation emphasized.
    02/2014; 1(1). DOI:10.1007/s40572-013-0002-8
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    • "Treatment of cells in vitro generates a defined epigenetic pattern, as evidenced by studies of induced pluripotent stem cells [73] and epithelial-to-mesenchymal transition [74]. The gut microbiome can alter the epigenetic pattern of the gut endothelial cells [75,76] by excreting signals that trigger a response. Likewise, a similar effect can be achieved in the oral cavity, which is under the constant influence of extrinsic factors and foreign agents from food intake. "
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    ABSTRACT: Periodontitis is a common oral disease that is characterized by infection and inflammation of the tooth supporting tissues. While its incidence is highly associated with outgrowth of the pathogenic microbiome, some patients show signs of predisposition and quickly fall into recurrence after treatment. Recent research using genetic associations of candidates as well as genome-wide analysis highlights that variations in genes related to the inflammatory response are associated with an increased risk of periodontitis. Intriguingly, some of the genes are regulated by epigenetic modifications, supposedly established and reprogrammed in response to environmental stimuli. In addition, the treatment with epigenetic drugs improves treatment of periodontitis in a mouse model. In this review, we highlight some of the recent progress identifying genetic factors associated with periodontitis and point to promising approaches in epigenetic research that may contribute to the understanding of molecular mechanisms involving different responses in individuals and the early detection of predispositions that may guide in future oral treatment and disease prevention.
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