Gene regulation by gonadal hormone receptors defines brain sex differences-[ATAC-Seq]

Estradiol establishes neural sex differences in many vertebrates and modulates mood, behavior, and energy balance in adulthood. In the canonical pathway, estradiol exerts its effects through the transcription factor estrogen receptor α (ERα). While 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 within a sexually dimorphic neural circuit that mediates social behaviors. 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 estradiol on brain development, behavior, and disease. Genomic response to estradiol in mouse brain

雌二醇（Estradiol）可在众多脊椎动物体内确立神经性别差异，并在成年个体中调节情绪、行为与能量平衡。在经典通路中，雌二醇通过转录因子雌激素受体α（estrogen receptor α，ERα）发挥其作用。尽管ERα已在乳腺癌研究中得到广泛表征，但其神经元靶标以及这些靶标在脑性别差异形成中的作用仍未得到充分阐明。本研究绘制了介导社交行为的性别二态性神经回路内基因组ERα结合位点的全面图谱。我们得出结论，ERα通过两种机制调控小鼠大脑的性别分化：一是确立两种雄性偏好性神经元类型，二是激活持续的雄性偏好性基因表达程序。综上，本研究结果揭示，基因表达的性别差异由神经元类固醇激素受体的激素激活所界定。我们所鉴定的分子靶标，可能是雌二醇影响大脑发育、行为与疾病的分子基础。小鼠大脑中雌二醇的基因组应答