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Epigenetics

Epigenetics is defined as heritable changes in gene expression that are, unlike mutations, not attributable to alterations in the sequence of DNA. The predominant epigenetic mechanisms are DNA methylation, modifications to chromatin, loss of imprinting and non-coding RNA. Epigenetic regulation of gene expression appears to have long-term effects and wide-ranging effects on health.1 There is a clear and prescient implication of benefits to both basic science and human health research that stems from a more complete understanding of the epigenome. These benefits have driven researchers to flock this field, and funding organizations have followed suit.

A large part of epigenetics is controlled by post-translational modifications on proteins. Methylations, acetylations, ubiquitination or phosphorylations lead to changes that for example influence transcription. Epigenetic modifications happen often during an organism’s lifetime; however, these changes can be transferred to the next generation if they occur in germ cells. Paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, changeable disorder or phenotypic severity, reprogramming, maternal attributes, carcinogenic processes, teratogenic effects, regulation of histone modifications, heterochromatin states and cloning are known to involve epigenetic processes.2

Fig. 1: Chromatin structure, including histones and DNA.

DNA Modifications

Covalent attachment of a methyl group to the C5 position of cytosine comprises the principal epigenetic modification of DNA. The presence of a methylated cytosine can repress transcription by inhibiting the binding of transcription factors or may promote the binding of other transcriptional repressors, including histone-modifying proteins, such as histone deacetylases.3

DNA demethylation plays an important role in development and tumorigenesis in mammals. DNA demethylation, occurring in primordial germ cells and in early embryos, is essential for cells to return to a pluripotent state.4

Histone Modifications

Similarly to DNA methylation, posttranslational histone modifications do not affect DNA nucleotide sequence but can modify its availability to the transcriptional machinery. Several types of histone modifications are known, amongst which acetylation, methylation, phosphorylation, and ubiquitination are the best studied and most important in terms of the regulation of chromatin structure and (transcriptional) activity. 5 While DNA methylation is considered to be a very stable epigenetic modification, histone modifications are comparably more labile with their levels being maintained by a balance between histone modifying enzymes, which add or remove specific modifications. Aberrant histone modification levels result from an imbalance in these modifying enzymes in diseased tissue, thus correcting the increased or decreased level of a particular enzyme will restore the natural balance in the affected cells.6

Chromatin Remodeling

The presence of histones acts as a barrier to protein access; thus chromatin remodeling must occur for essential processes such as transcription and replication. In conjunction with histone modifications, DNA methylation plays critical roles in gene silencing through chromatin remodeling. Chromatin remodeling is also interconnected with the DNA damage response, maintenance of stem cell properties, and cell differentiation programs. Chromatin modifications have increasingly been shown to produce long-lasting alterations in chromatin structure and transcription. Recent studies have shown environmental exposures in utero have the potential to alter normal developmental signaling networks, physiologic responses, and disease susceptibility later in life during a process known as developmental reprogramming.7

Transcription Factors

Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. They (often) utilize cosubstrates generated by cellular metabolism, thereby providing a potential link between nutrition, metabolism, and gene regulation.8

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References

  • (1) Hamilton JP. Epigenetics: principles and practice. Dig Dis. 2011;29(2):130-135. doi:10.1159/000323874)
  • (2) Moosavi A, Motevalizadeh Ardekani A. Role of Epigenetics in Biology and Human Diseases. Iran Biomed J. 2016;20(5):246-258. doi:10.22045/ibj.2016.01
  • Loscalzo J, Handy DE. Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series). Pulm Circ. 2014;4(2):169-174. doi:10.1086/675979
  • Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy?. Genes Cancer. 2011;2(6):607-617. doi:10.1177/1947601910393957
  • (5) Alaskhar Alhamwe B, Khalaila R, Wolf J, et al. Histone modifications and their role in epigenetics of atopy and allergic diseases. Allergy Asthma Clin Immunol. 2018;14:39. Published 2018 May 23. doi:10.1186/s13223-018-0259-4
  • (6) Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol. 2010;28(10):1069-1078. doi:10.1038/nbt.1678
  • (7) Bariar B, Vestal CG, Richardson C. Long-term effects of chromatin remodeling and DNA damage in stem cells induced by environmental and dietary agents. J Environ Pathol Toxicol Oncol. 2013;32(4):307-327. doi:10.1615/jenvironpatholtoxicoloncol. 2013007980
  • Kaelin WG Jr, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153(1):56-69. doi:10.1016/j.cell.2013.03.004
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