Sex-Specific Induction of H3K27me1 in the Prefrontal Cortex Mediates the Enduring Effects of Early Life Stress

ABSTRACT Early life stress (ELS) is a strong risk factor for several neurodevelopmental and psychiatric disorders and is associated with persistent molecular alterations in corticolimbic regions, including the prefrontal cortex (PFC). Here, we combined unbiased proteomics profiling and viral-mediated gene transfer to characterize the enduring epigenetic changes in the PFC of male and female mice previously exposed to ELS. We found that ELS induced sex-specific and age-dependent accumulation of monomethylation of lysine 27 at histone H3 (H3K27me1), with a transient increase in adolescent females, and a delayed but enduring effect in adult males. ELS-induced H3K27me1 accumulation in the PFC involved changes of SUZ12, a subunit of the polycomb repressive complex 2 (PRC2), which controls H3K27 methylation patterns. Indeed, expression of the catalytic domain of SUZ12, VEFS, in PFC neurons during adolescence led to sex differences in social and cognitive alterations in adulthood. Together, our results demonstrate that H3K27me1 functions as a “chromatin scar” in the PFC, where it mediates lifelong susceptibility to ELS in a sex-specific manner.