Growing evidence supports the hypothesis that epigenetics is a key mechanism through which environmental exposures interact with an individual’s genetic constitution to determine risk for depression throughout life.1 Epigenetics, in its broadest meaning, refers to stable changes in gene expression that are mediated via altered chromatin structure without modification of DNA sequence. According to this hypothesis, severe stress triggers changes—in vulnerable individuals—in chromatin structure at particular genomic loci in the brain’s limbic regions, which drive sustained changes in gene expression that contribute to episodes of depression. A corollary of this hypothesis is that such stress-induced epigenetic modifications also occur early in life and help determine an individual’s lifetime vulnerability or resistance to subsequent stressful events.
A, The eukaryotic genome is organized by wrapping DNA around histone octamers to form the basic units of chromatin, nucleosomes, which are then further organized and compacted into higher-ordered structures. B, The histone octamer consists of 2 copies each of H2A, H2B, H3, and H4. In addition to globular domains, they each have N-termini tails that protrude from the nucleosome, while H2A also has a C-terminal tail. These tails can be posttranslationally modified, and major forms of mammalian acetylation and methylation modifications on lysine residues on each tail are highlighted. The molecules are drawn approximately proportional to the size of the protein, although the number of residues shown is not meant to reflect the exact size of the N-terminal tails. This image was published in Sun HS, Kennedy PJ, Nestler EJ. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology Rev. 2013;38:124-137. The author retains the copyright.
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