Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour. Academic Article uri icon


  • Sex differences are found in brain structure and function across species, and across brain disorders in humans 1-3 . The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan 4 . 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 5-7 . However, due to limited molecular studies in female rodents 8 , very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that overexpressing Egr1, a candidate oestrous cycle-dependent transcription factor 9 , induces sex-specific changes in ventral hippocampal neuronal chromatin, gene expression, and synaptic plasticity, along with hippocampus-dependent behaviours. Importantly, Egr1 overexpression mimics the high-oestrogenic phase of the oestrous cycle, and affects behaviours in ovarian hormone-depleted females but not in males. We demonstrate that Egr1 opens neuronal chromatin directly across the sexes, although with limited genomic overlap. Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation 1 in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.

published proceedings

  • bioRxiv

altmetric score

  • 36.2

author list (cited authors)

  • Rocks, D., Purisic, E., Gallo, E. F., Greally, J. M., Suzuki, M., & Kundakovic, M.

citation count

  • 1

complete list of authors

  • Rocks, Devin||Purisic, Eric||Gallo, Eduardo F||Greally, John M||Suzuki, Masako||Kundakovic, Marija

publication date

  • December 2023