Gene regulation by gonadal hormone receptors underlies brain sex differences

Abstract

Oestradiol establishes neural sex differences in many vertebrates1–3 and modulates mood, behaviour and energy balance in adulthood4–8. In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα)9. Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of oestradiol on brain development, behaviour and disease.

Dynamic molecular evolution of a supergene with suppressed recombination in white-throated sparrows

“…Two out of the fifteen genes inside the balanced ZAL2 m outlier region showed signatures of differential gene expression between the haplogroups. One of these genes is GREB1 , which in mammals is a downstream target of ERα ( Gegenhuber et al, 2022 ). This finding is notable because, in white-throated sparrows, ERα is causally related to the behavioral differences between morphs ( Merritt et al, 2020 ; Horton et al, 2014 ).…”

An allostatic epigenetic memory on chromatin footprints after double-hit acute stress

“…Indeed, we shed light on epigenomic marks of stress across the genome, particularly in ARE and GRE sites, that differentially persist over time in males and females and that epigenetically respond to a subsequent stressor occurring in a different context. Since hormonal activation of neuronal steroid receptors defines sex differences in gene expression ( Gegenhuber et al, 2022 ), further studies are needed to isolate the role of gonadal hormones in chromatin reorganization after double-hit stress. One speculation is that the higher epigenomic reactivity that these findings show in females compared to males may underlie the genomics behind the likelihood to develop PTSD in humans, whose prevalence is twice higher in women than in men ( Olff, 2017 ).…”

DMRT Transcription Factors in the Control of Nervous System Sexual Differentiation

“…According to the organizational-activational hypothesis of brain sexual differentiation (Arnold, 2009 ), during the organizational phase, several mechanisms will configure dimorphic circuits, such as proliferation, neurogenesis, apoptosis, dendritic growth, synaptogenesis or synaptic pruning among others (Phoenix et al, 1959 ; Arnold, 2009 ; McCarthy et al, 2017 ). Later, in sexually mature adult animals, both testosterone and estradiol (released by adult Leydig cells and by granulosa cells, respectively) will modulate brain activity during the activational phase (McCarthy, 2020 ; Gegenhuber et al, 2022 ). Therefore, transcriptional networks—potentially including Dmrt genes—that affect gonadal development and maintenance could indirectly have a major impact on sexual brain differentiation.…”