Regulation of neural gene expression by estrogen receptor alpha

The transcription factor estrogen receptor α (ERα) is a principal regulator of sex differences in the vertebrate brain and can modulate mood, behavior, and energy balance in females and males. However, the genes regulated by ERα in the brain remain largely unknown. Here we reveal the genomic binding of ERα within a sexually dimorphic neural circuit that regulates social behaviors. We profiled gene expression and chromatin accessibility and show ERα induces a neurodevelopmental gene program in adulthood. We further demonstrate that ERα binds with Nuclear factor I X-type (Nfix) to regulate a male-biased gene expression program that initiates in early life. Our results reveal a neural strategy for ERα-mediated gene regulation and provide molecular targets that underlie estrogen’s effects on brain development, behavior, and disease.