Sex-specific hormone-sensitive regulatory architecture in adolescence as a scaffold for depression vulnerability

Adolescence is a critical developmental period during which sex differences in depression risk emerge, yet the underlying molecular mechanisms remain unclear. Here, we integrated longitudinal transcriptomic, epigenomic, and gene regulatory network analyses to characterize sex-specific regulatory dynamics of the brain across adolescence under normative conditions and elucidate how baseline molecular differences may shape later vulnerability. We observed that immediate early genes exhibited the strongest sex-biased signals, with males and females showing opposing developmental trajectories, suggesting a role in sex-specific stress-responsive programs. Across analyses, a consistent pattern emerged: males showed stronger activity-dependent neuronal signatures, whereas females showed stronger stress- and immune-related signatures. Extending these findings to a disease context using single-nucleus chromatin accessibility data, we identified hormone-responsive regulatory elements enriched in depression-associated regions, with sex- and cell type-specific links to genetic risk. Grounded in established models of sex-specific stress responses, these findings offer a developmental regulatory framework for understanding the differential presentation of, and vulnerability to, depression.