Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking.

The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca-activated K (K2 or SK) channels encoded by the family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol dependent mice. Here, this cross-species analysis focused on DNA methylation, gene expression, and single nucleotide polymorphisms including alternative promoters in that could influence surface trafficking and function of K2 channels. Bisulfite sequencing analysis of the nucleus accumbens tissue from alcohol-drinking monkeys and alcohol dependent mice revealed a differentially methylated region in exon 1A of that overlaps with a predicted promoter sequence. The hypermethylation of in the accumbens paralleled an increase in expression of alternative transcripts that encode apamin-insensitive and dominant-negative K2 channel isoforms. A polymorphic repeat in macaque encoded by exon 1 did not correlate with alcohol drinking. At the protein level, K2.3 channel expression in the accumbens was significantly reduced in very heavy drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of represent a complex mechanism that utilizes alternative promoters to impact firing of accumbens neurons. Thus, these results provide support for hypermethylation of as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.