What Is Epigenetics?

Epigenetics is a field of biology concerned with heritable changes in gene expression that arise without alteration to the underlying DNA nucleotide sequence. Where classical genetics focuses on the information encoded in the sequence of adenine, thymine, guanine, and cytosine bases, epigenetics studies the chemical modifications superimposed on DNA and on the histone proteins around which DNA is wrapped, modifications that determine whether and how strongly particular genes are expressed in a given cell type, developmental stage, or environmental context. The NHGRI Genetics Glossary defines epigenetics as examining changes to DNA that do not involve alterations to the underlying sequence yet can be inherited through cell division.

The field occupies a critical position between genetics and environmental biology. An organism's genome is largely fixed at conception, yet identical twins diverge in gene expression patterns over time as their epigenomes accumulate different modifications in response to diet, stress, toxin exposure, and other environmental inputs. Epigenetics provides the molecular mechanism through which nurture modifies nature.

DNA Methylation

DNA methylation is the best-characterized epigenetic mechanism. It involves the covalent addition of a methyl group, a carbon atom bonded to three hydrogen atoms, to the fifth position of cytosine residues, predominantly at cytosine-guanine dinucleotide (CpG) sites across the genome. Methylation at gene promoter regions generally silences transcription by blocking transcription factor binding or by recruiting proteins that compact the chromatin structure.

Genome-wide methylation patterns are established during embryonic development and are maintained by a family of DNA methyltransferase enzymes as cells divide. The fidelity of this maintenance is not absolute: methylation patterns drift with age and in response to environmental exposures, contributing to the age-related changes in gene expression patterns that underlie many chronic diseases. Aberrant methylation, including hypermethylation of tumor suppressor genes, is a consistent feature of cancer cells and is a target of epigenetic therapy.

Histone Modification and Chromatin Remodeling

DNA in the nucleus is packaged around octameric histone protein complexes, forming nucleosomes that condense DNA into manageable lengths. The amino-terminal tails of histone proteins protrude from the nucleosome core and are subject to dozens of post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitination. These marks are added and removed by enzyme families that write, read, and erase the histone code.

Histone acetylation at lysine residues generally correlates with transcriptional activation by loosening the compaction of the chromatin fiber and recruiting transcriptional machinery. Histone methylation can either activate or repress transcription depending on the specific residue modified and the degree of methylation. A comprehensive review in PMC on epigenetic principles and practice details how combinations of histone marks at regulatory elements constitute a combinatorial code that determines cell-type-specific gene expression programs.

Non-Coding RNA

A third layer of epigenetic regulation operates through non-coding RNA molecules that do not encode proteins but influence gene expression at transcriptional and post-transcriptional levels. MicroRNAs, small interfering RNAs, and long non-coding RNAs interact with the transcription machinery and with messenger RNA stability to fine-tune protein output. CDC resources on epigenetics and health document how disruption of non-coding RNA regulation contributes to developmental disorders and disease susceptibility. Certain small RNA-mediated silencing states can persist across generations, making non-coding RNAs a vehicle for transgenerational epigenetic inheritance.

Applications

Epigenetics has applications in a range of fields, including:

• Cancer biomarker development and epigenetic drug targeting
• Developmental biology and stem cell reprogramming
• Toxicological risk assessment of environmental chemical exposures
• Aging research and the biology of age-related disease
• Forensic identification and tissue-type determination from biological samples