Epigenetic regulation of sex differences in the brain

我们的资助申请测试了大脑性别差异受表观遗传事件调节的假设 在围产期的关键时期在包括老鼠在内的许多脊椎动物中， 在生命的最初几天里受到雌激素信号的控制。用雌激素治疗新生儿女性 不可逆转地使成年人的社会行为和基因表达男性化。然而，所使用的分子策略 雌激素对大脑产生持久影响的机制还知之甚少。本提案的目的是确定 两个性别二态性脑区基因表达和染色质的性别差异。后 终纹床核（BNST）和内侧杏仁核（MeA）的分裂高度 在新生儿雌激素的控制下发育并调节先天性别的相互关联的大脑区域- 特定的社会行为，如交配和攻击。我们假设新生儿雌激素 男性特异性染色质状态，从根本上改变了神经元的细胞特性，从而改变了它们在 行为电路我们将通过基因表达的全基因组分析来验证这一假设， 在幼仔和成人中，ERα表达神经元中特异性染色质。在具体目标1中，我们将确定 BNST/MeA中的性别特异性基因程序，并探索这些程序是如何通过 雄性和雌性体内不同的成年激素分布。在具体目标2中，我们将确定顺式调节元件， 例如增强子，并研究转录因子的性别差异 这些元素的使用。在具体目标3中，我们将测试一种新的两性异形体的需求。 转录因子在基因表达和行为中产生性别差异。综合来看，我们的发现 将揭示雌激素信号在生命早期如何永久影响成年基因表达， 最终，性别特异性行为。这项工作将提供洞察如何在一个关键的瞬态事件 发育期对成年期的大脑和行为有重大影响。这一关键时期 永久性地影响大脑结构和功能，这表明精神疾病的性别差异， 如自闭症和抑郁症，可能起源于大脑的性别分化。

Our grant application tests the hypothesis that sex differences in the brain are regulated by epigenetic events during a perinatal critical period. In many vertebrates, including mice, sex-specific neural circuitry develops under the control of estrogen signaling during the first few days of life. Treating neonatal females with estrogen irreversibly masculinizes adult social behavior and gene expression. However, the molecular strategies used by estrogen to exert lasting effects on the brain are poorly understood. The goal of this proposal is to identify sex differences in gene expression and chromatin in two sexually dimorphic brain regions. The posterior division of the bed nucleus of the stria terminalis (BNST), and the medial amygdala (MeA) are highly interconnected brain regions that develop under the control of neonatal estrogen and regulate innate sex- specific social behaviors such as mating and aggression. We hypothesize that neonatal estrogen generates male-specific chromatin states that fundamentally alter the cellular identity of neurons and thus their function in behavioral circuitry. We will test this hypothesis through genome-wide analysis of gene expression and chromatin specifically in ERα-expressing neurons in both pups and adults. In Specific Aim 1 we will determine the sex-specific gene programs in the BNST/MeA and explore how these programs are acutely modulated by distinct adult hormonal profiles in males and females. In Specific Aim 2 we will identify cis-regulatory elements, such as enhancers, in ERα neurons from BNST/MeA, and investigate sex differences in transcription factor occupancy of these elements. In Specific Aim 3 we will test the requirement for a novel sexually dimorphic transcription factor in generating sex differences in gene expression and behavior. Taken together, our findings will reveal how estrogen signaling during early life permanently influences adult gene expression and ultimately, sex-specific behaviors. This work will provide insight into how a transient event during a critical developmental period can have significant impact on the brain and behavior in adulthood. This critical period permanently affects brain structures and function, suggesting that sex differences in psychiatric disorders, such as autism and depression, may originate during sexual differentiation of the brain.