In humans with alcohol use disorders (AUD), stress often triggers craving and relapse to alcohol drinking. This characteristic can be modeled in laboratory using stress-induced reinstatement. Here, we showed that in both male and female rats, an increased sensitivity to develop stress-induced reinstatement is promoted by decreased expression of Prdm2, a gene that encodes histone methyltransferase, due to alcohol-induced DNA hypermethylation in the dorsomedial prefrontal cortex (dmPFC). Consistent with our preclinical data, we found that humans with AUD had lowered PRDM2 expression in the prefrontal cortex compared to controls. We are now examining DNA methylation status of PRDM2 promoters. Together, this highlights the role of PRDM2 in AUD. We further aim to identify the neural projection through which lowered Prdm2 expression promotes stress-induced reinstatement. Substantial evidence indicates that stress responses are mediated by the dmPFC projection to the basolateral amygdala (dmPFC-BLA). Recently, we found that synaptogenesis of this projection is dysregulated by lowered Prdm2 expression. Another potential projection is the dmPFC projection to the nucleus accumbens core (NAcC), which has been reported to be involved in footshock-induced reinstatement of cocaine seeking. Using an intersectional viral-mediated knockdown technique, we found that downregulation of Prdm2 in the dmPFC-BLA neurons was not sufficient to promote stress-induced reinstatement. We are now investigating the functional role of Prdm2 knockdown in the dmPFC-NAcC neurons. Overall, our findings suggest that lowered Prdm2 expression may enhance susceptibility to stress-induced alcohol relapse-like behaviors through the projection of the dmPFC, and that the effect of Prdm2 may translate across species.