2 Neuroscience2.9 Genetics
2.9.6 Epigenetics
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Written by Resident Doctor Committee · Published
Definition
Epigenetics is heritable change in gene expression and phenotype without any change in the DNA sequence.
The marks sit on DNA or chromatin, chiefly cytosine methylation and histone tail modification, with chromatin remodelling and regulatory RNA acting alongside.
Heritable usually means passed between daughter cells, not between generations.
Process | Why it is not epigenetic |
|---|---|
Glycation | Sugar attaches, unregulated, to proteins outside chromatin |
Mutations, copy number variants, repeat expansions | They change the DNA sequence |
DNA methylation
DNA methylation adds a methyl group to the 5 position of cytosine, mostly at CpG sites, and CpG islands often lie near promoters.
Promoter methylation represses transcription by blocking transcription factor binding and recruiting repressive complexes.
Maintenance enzymes copy methylation patterns after DNA replication, so marks persist through cell division, while de novo enzymes lay down new marks.
Monozygotic twins can become discordant in phenotype because different environmental exposures alter their methylation despite identical sequences.
Histone modification
Change | Chromatin | Gene expression |
|---|---|---|
Increased lysine acetylation | Opens | Rises |
Loss of acetylation at a promoter | Condenses | Silenced |
Histone 3 lysine 4 trimethylation | Marks active promoters | Active |
Histone 3 lysine 9 or 27 trimethylation | Compacts | Repressed |
CpG hypomethylation, like increased acetylation, raises expression.
Acetyltransferases add acetyl groups and deacetylases remove them, and valproate inhibits histone deacetylases.
Imprinting
Imprinting uses germline marks to silence one parental allele.
At 15q11 to 13, loss of paternal expression causes Prader-Willi syndrome and loss of the maternal contribution causes Angelman syndrome.
Schizophrenia
The best-replicated finding is promoter hypermethylation of GABAergic genes (reelin, GAD67) and brain-derived neurotrophic factor (BDNF), with raised DNA methyltransferase 1 (DNMT1).
These post-mortem associations do not establish cause.
Early adversity and the stress axis
Methylation of the glucocorticoid receptor gene (NR3C1) promoter after early adversity silences the gene and weakens hypothalamic-pituitary-adrenal feedback.
Maintenance enzymes copy this mark through cell division, so it can explain a lasting effect of childhood adversity on the stress axis.
Meaney's high-care rat pups had lower hippocampal glucocorticoid receptor methylation and smaller adult stress responses, and cross-fostering showed the cause was environmental.
Human post-mortem findings in people who were abused remain observational.