Epigenetics is the study of molecular and cellular mechanisms that influence gene activity without changing the underlying DNA nucleotide sequence. The term generally refers to heritable or persistent changes in gene regulation involving mechanisms such as DNA methylation, histone modification, chromatin organisation and regulatory noncoding RNAs. Epigenetic mechanisms help determine which genes are active, inactive or expressed at particular levels in particular cells.
This is essential because nearly all cells in a multicellular organism contain essentially the same genome, yet a neuron, muscle cell and liver cell have very different structures and functions. Their differences arise partly because different sets of genes are expressed. Epigenetic regulation provides one layer of control that helps establish and maintain these patterns of gene activity during development and throughout life.
DNA methylation is one of the best studied epigenetic mechanisms. It commonly involves the addition of a methyl group to cytosine bases at sites called CpG sites in vertebrate genomes. Methylation patterns can influence the accessibility of DNA and the recruitment of proteins involved in gene regulation. Promoter methylation is often associated with reduced transcription when it occurs in particular regulatory contexts, although methylation does not have one universal effect in every genomic location.
DNA methylation patterns are established and maintained by specialised enzymes and can be modified through active and passive processes. Methylation is important in development, genomic imprinting, X chromosome inactivation, suppression of certain repetitive sequences and cellular differentiation. Abnormal methylation patterns are also observed in many diseases, including cancer.
Histones are proteins around which DNA is wrapped to form chromatin. Chemical modifications of histone proteins can influence how tightly DNA is packaged and how accessible particular genomic regions are to transcription machinery. Examples include acetylation, methylation, phosphorylation and ubiquitination of specific amino acid residues. Histone acetylation at particular sites is often associated with more accessible chromatin and active transcription, whereas some histone methylation marks correlate with activation and others with repression depending on the modified residue and surrounding context. Enzymes that add, remove or interpret these modifications are sometimes described as writers, erasers and readers. The combined pattern of chromatin modifications contributes to a regulatory environment that influences whether genes can be efficiently transcribed.
Chromatin structure provides another major level of epigenetic regulation. DNA is packaged into nucleosomes and progressively organised into higher order structures within the nucleus. Chromatin can exist in relatively accessible regions associated with active gene expression and more condensed regions associated with reduced accessibility. ATP dependent chromatin remodelling complexes can reposition or alter nucleosomes, changing access to DNA sequences. Three dimensional genome organisation also brings distant regulatory elements into physical proximity with genes, allowing enhancers and other control regions to influence transcription. Epigenetics therefore cannot be reduced simply to DNA methylation. It encompasses a network of molecular processes affecting chromatin accessibility, chromosome organisation, transcription and cellular identity.
Epigenetic regulation is especially important during development. Early developmental cells can acquire different gene expression programmes as they differentiate into specialised cell types. These programmes are stabilised partly through epigenetic mechanisms, allowing a differentiated cell to maintain its identity while retaining essentially the same DNA sequence as other cells. Genomic imprinting provides a particularly distinctive example because certain genes can be expressed differently depending on whether the inherited copy came from the mother or father.
X chromosome inactivation in female mammals is another major epigenetic phenomenon in which one X chromosome is largely silenced in many cells to balance gene dosage between XX and XY individuals. These processes demonstrate that gene activity depends not only on DNA sequence but also on regulatory information associated with chromatin.
Environmental and physiological factors can influence epigenetic states. Nutrition, hormones, inflammation, ageing, stress, toxins and other exposures have all been investigated for potential effects on DNA methylation, histone modifications and chromatin organisation. However, claims about environmental experiences producing permanent inherited epigenetic changes in humans require careful evidence because many observed molecular associations are tissue specific, transient or influenced by confounding factors. Epigenetic states can change during an individual's lifetime and can be reset during parts of reproduction and early development. Therefore, epigenetics should not be presented as a mechanism by which experiences simply rewrite genes or permanently encode all environmental effects. The relationship between environment, epigenetic regulation and phenotype is complex and depends strongly on biological context.
Epigenetic abnormalities are associated with disease, particularly cancer. Tumour cells can show widespread changes in DNA methylation and histone modification, including inappropriate silencing of tumour suppressor genes and abnormal activation of other regulatory programmes. Some medicines have been developed to target enzymes involved in epigenetic regulation, including DNA methyltransferases and histone deacetylases. Epigenetic mechanisms are also investigated in neurological disease, metabolic disorders, developmental conditions and immune disorders. Importantly, an epigenetic association does not necessarily demonstrate that an epigenetic change causes a disease. Disease processes can themselves alter cellular states, and environmental or genetic factors can influence both epigenetic marks and disease risk. Experimental studies therefore distinguish correlation from causal mechanisms.
Epigenetics is closely related to genetics but is not synonymous with gene mutation or DNA sequence variation. A mutation changes the nucleotide sequence, whereas an epigenetic modification generally changes the regulation or packaging of DNA without altering its nucleotide sequence. Epigenetic states can sometimes be mitotically inherited when cells divide, allowing daughter cells to retain a particular expression programme.
Some epigenetic information can also persist across generations in particular biological circumstances, but widespread claims of stable transgenerational inheritance in humans require strong evidence. Modern epigenetics combines molecular biology, genetics, developmental biology, cell biology and genomics. Its significance lies in explaining how cells use the same basic genome to produce different patterns of gene expression and how those regulatory patterns can change during development, disease and environmental response.
