Egr1 is a sex-dependent regulator of neuronal chromatin, structural plasticity, and behaviour.

Sex differences are found in brain structure and function across species, and across brain disorders in humans. A major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan. Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk. However, due to limited molecular studies in female rodents, very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that ventral hippocampal (vHIP) overexpression of Egr1, an oestrous cycle-dependent transcription factor, induces sex-dependent changes in vHIP neuronal chromatin, gene expression, and structural plasticity, along with female-specific effects on vHIP-dependent behaviours. Importantly, Egr1 overexpression and knockdown partially mimic the vHIP chromatin state associated with the high and low-oestrogenic phase of the oestrous cycle, respectively. We demonstrate that Egr1 directs neuronal chromatin opening across the sexes, although with limited genomic overlap. Our study not only reveals a sex-dependent chromatin regulator in the brain, but also provides functional evidence that this sex-dependent gene regulation drives structural and behavioural plasticity, informing sex-based treatments for brain disorders.