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
    • "At a chromatin level it has been shown that, thanks to histone modifications, the APOC3 enhancer maintains an active chromatin subdomain in the cluster facilitating the enhancer to reach the APOA1, APOC3 and APOA4 gene promoters [28]. Another epigenetic mark such as cytosine methylation of CpG dinucleotides of DNA, can be influenced by environmental factors and regulate gene expression levels in response to external stimuli [29]. For that, we hypothesize that the tissue-specific expression of the APOA1/C3/A4/A5 gene cluster will show an inverse pattern with DNA methylation, and that repression in non-or low-expressing tissue, such as the intestine, can be reversed using epigenetic drugs, which may have potential implications for the prevention and treatment of hypertriglyceridemia. "
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    ABSTRACT: Objective: The tissue-specific expression profiles of genes within the APOA1/C3/A4/A5 cluster play an important role in lipid metabolism regulation. We hypothesize that the tissue-specific expression of the APOA1/C3/A4/A5 gene cluster will show an inverse pattern with DNA methylation, and that repression in non- or low-expressing tissue, such as the intestine, can be reversed using epigenetic drugs. Methods and results: We analyzed DNA samples from different human adult tissues (liver, intestine, leukocytes, brain, kidney, pancreas, muscle and sperm) using the Infinium HumanMethyation450 BeadChip array. DNA methylation profiles in APOA1/C3/A4/A5 gene cluster were confirmed by bisulfite PCR and pyrosequencing. To determine whether the observed tissue-specific methylation was associated with the expression profile we exposed intestinal TC7/Caco-2 cells to the demethylating agent 5-Aza-2'-deoxycytidine and monitored intestinal APOA1/C3/A4/A5 transcript re-expression by RT-qPCR. The promoters of APOA1, APOC3 and APOA5 genes were less methylated in liver compared to other tissues, and APOA4 gene was highly methylated in most tissues and partially methylated in liver and intestine. In TC7/Caco-2 cells, 5-Aza-2'-deoxycytidine treatment induced a decrease between 37 and 24% in the methylation levels of APOA1/C3/A4/A5 genes and a concomitant re-expression mainly in APOA1, APOA4 and APOA5 genes ranging from 22 to 600%. Conclusions: We have determined the methylation patterns of the APOA1/C3/A4/A5 cluster that may be directly involved in the transcriptional regulation of this cluster. DNA demethylation of intestinal cells increases the RNA levels especially of APOA1, APOA4 and APOA5 genes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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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.
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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.
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