Figure 4. Effects of alcohol exposure on histone methylation.

A) Acute ethanol decreases G9A expression and H3K9me2 and leads to open chromatin and increased NPY expression and decreased anxiety-like behavior. Rapid ethanol tolerance by administering an ethanol challenge restores normal H3K9me2 and normal anxiety-like behavior. G9A inhibitors decrease H3K9me2 and lead to decreased anxiety-like behavior. B) Chronic ethanol primarily causes changes via repressive histone methylation (e.g. H3K9me2, H3K9me3, and H3K27me3) however some human and rodent studies have observed an increase in H3K4me3. Ethanol decreases the expression of PRDM2, LSD1 and KDM6B. LSD1 demethylates H3K9me2 and H2K9me1 while KDM6B demethylates H3K27me3. G9A, conversely, methylates H3K9 to H3K9me1 and H3K9me2. The net result is condensed chromatin and decreased gene transcription of neuropeptide y (Npy), activity-regulated cytoskeleton-associated protein (Arc), brain derived neurotrophic factor (Bdnf), choline acetyltransferase (Chat), and tropomyosin receptor kinase A (TrkA). This is associated with anxiety-like behavior, alcohol consumption, deficits in reversal learning, and craniofacial deformities (when given during prenatal development). Exercise, choline or G9A inhibitors can reverse these changes. In ethanol naïve animals, knockdown of PRDM2, LSD1, and KDM6B leads to increased anxiety-like behavior and/or drinking. In humans, EZH2 is shown to bind to regulatory elements of ARC and BDNF and increase repressive H3K27me3.