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Review
. 2018 Apr 5;378(14):1323-1334.
doi: 10.1056/NEJMra1402513.

The Key Role of Epigenetics in Human Disease Prevention and Mitigation

Andrew P Feinberg  1
Affiliations
Review

The Key Role of Epigenetics in Human Disease Prevention and Mitigation

Andrew P Feinberg. N Engl J Med. .
No abstract available

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Figures

Figure 1.
Figure 1.. The Cellular Nature of Epigenetic information.
The DNA double helix is modified at the nucleotide cytosine by DNA methylation (brown dots). The nucleosomes around which the DNA is coiled undergo post-translational modifications of their component histones (green dots, depicting activation marks; red dots depict silencing marks), leading to gene activation (light-blue nucleosomes, with RNA transcripts originating nearby) or silencing (dark-blue nucleosomes). Higher-order chromatin structure involves nucleosomal compaction often near the nuclear membrane (heterochromatin) or nucleosomal accessibility (euchromatin). The nuclear periphery is primarily repressive but probably also contains transcriptionally permissive subcompartments. Higher-order large blocks of heterochromatin often involve large epigenomic domains termed lamina-associated domains (LADs) and large, organized chromatin lysine (K) modifications (LOCKs). In cancer, both large and smaller heterochromatic domains become euchromatic. In addition, epigenetic modulators such as environmental exposure and aging, as well as cancer mutations in epigenetic modifier genes, affect the expression of epigenetic mediators controlling pluripotency and cellular self-renewal. All these factors lead to increased stochastic gene expression in cancer, promoting tumor-cell heterogeneity and cancer-cell survival in a changing environment (e.g., as a result of metastasis or chemotherapy).
Figure 2.
Figure 2.. Epigenetic Approach to Epidemiology.
Common diseases in humans (e.g., cancer, diabetes, and rheumatoid arthritis) can be better understood through the combination of conventional genomewide association studies and epigenome-wide association studies. Conventional genomewide association studies (Panel A) link a hereditary DNA sequence variant or single-nucleotide polymorphism (SNP), through a presumed connection to a gene, to a disease phenotype (e.g., diabetes). Epigenome-wide association studies (Panel B) link environmental exposures (for which establishing causality requires statistical tools, animal models, or biochemical studies) and aging to a DNA methylation change and subsequently to a disease phenotype (e.g., diabetes or rheumatoid arthritis). An integrated approach (Panel C) incorporates both genetic and environmental exposure by relating genetic variants to epigenetic changes (methylation quantitative trait locus [meQTL]) in disease (e.g., diabetes and rheumatoid arthritis). Moreover, the combination of genomewide and epigenome-wide association studies can identify genetic variants regulating epigenetic marks (clusters of DNA methylation under genetic control [GeMes]) across linkage disequilibrium blocks that are normally penalized mathematically in conventional genomewide association studies (i.e., even though they are not in the same linkage disequilibrium block and thus not normally considered associated, they can be topologically associated through higher-order folding of chromatin in the nucleus, as shown in example 2). Similarly, cancer epigenetics (Panel D) enriches conventional cancer genetics by including environmental exposure and epigenetic changes together with hereditary genetic variants in risk assessment. DMR denotes differentially methylated region.
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Comment in

References

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