Alternative Polyadenylation in the Brain is Modulated by Chronic Ethanol Exposure in a Sex- and Cell Type-Specific...

Alternative polyadenylation (APA) is a common posttranscriptional mechanism to regulate gene expression. APA generates mRNA isoforms that differ in 3' UTR length or, through alternative last exons, encode distinct protein carboxyl termini. This is especially consequential in neurons, where these isoforms are often asymmetrically localized to dendrites and axons and can be locally translated. Whether alcohol dependence induces APA, however, remains to be explored. Here, we investigated APA changes in alcohol dependence using a mouse model characterized by increased voluntary drinking after chronic intermittent ethanol (CIE) exposure. We examined APA during protracted withdrawal from alcohol in three brain regions of male and female mice. Our analyses revealed hundreds of genes undergoing APA in males, but substantially fewer in females, suggesting sex-specific effects of CIE on APA. Notably, male and female mice displayed distinct APA signatures. APA genes were different from differentially expressed genes (DEGs), suggesting that these molecular processes are regulated independently. We also determined that the expression of APA genes was associated primarily with neurons, while DEGs were associated with nonneuronal cells. Many of the APA genes were involved in synaptic integrity, neuroplasticity, and neuronal maintenance, which was consistent with their enrichment in neurons. Our study suggests that APA is a crucial sex- and cell type-specific mechanism in alcohol dependence with the potential to influence localized neuronal protein expression during protracted withdrawal and to modify alcohol consumption behavior.