Epigenetic regulation of sex differences in the brain

大脑性别差异的表观遗传调控

• 批准号: 10087962
• 负责人: Jessica Tollkuhn
• 金额: $ 48万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087962
• 关键词: Acute; Adult; Affect; Age of Onset; Aggressive behavior; Alleles; Amygdaloid structure; Anxiety; Applications Grants; Atlases; Behavior; Behavioral; Birth; Brain; Brain region; Cell Nucleus; Chromatin; Development; Elements; Enhancers; Epigenetic Process; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Event; Female; Feminization; Foundations; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; Hormonal; Hormone Responsive; Hormones; Hypothalamic structure; Incidence; Knowledge; Label; Laboratories; Libido; Life; LoxP-flanked allele; Masculine; Medial; Mediating; Mental Depression; Mental disorders; Molecular; Mus; Neonatal; Neurons; Nuclear Receptors; Partner in relationship; Pattern; Perinatal; Prognosis; Puberty; Regulatory Element; Role; Schizophrenia; Severities; Sex Bias; Sex Differences; Sex Differentiation; Signal Transduction; Social Behavior; Specific qualifier value; Steroid Receptors; Structure; Structure of terminal stria nuclei of preoptic region; Territoriality; Testing; Testosterone; Tissues; Vertebrates; Work; autism spectrum disorder; behavior influence; bioinformatics tool; brain behavior; cell type; critical developmental period; critical period; differential expression; epigenetic regulation; epigenome; epigenomics; experimental study; genome-wide analysis; hormone regulation; inhibitory neuron; insight; male; mouse model; mutant; neural circuit; novel; postnatal; programs; pup; sex; sexual dimorphism; sexual identity; steroid hormone; transcription factor; transcriptome; whole genome

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.

我们的拨款申请测试了大脑中的性别差异是由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，性别特异的神经回路会发育 在生命的最初几天，在雌激素信号的控制下。雌激素治疗新生儿期女性 不可逆转地使成年人的社会行为和基因表达男性化。然而，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。这项提案的目标是确定 性别差异的基因表达和染色质在两个性别二型性脑区。后部 终纹床核(BNST)和杏仁内侧核(MEA)高度分裂 在新生儿雌激素的控制下发育并调节先天性别的相互连接的大脑区域- 特定的社会行为，如交配和攻击性。我们假设新生儿雌激素会产生 男性特有的染色质状态，从根本上改变神经元的细胞身份，从而改变它们在 行为回路。我们将通过全基因组范围的基因表达和分析来验证这一假设 染色质在幼鼠和成体的ERα表达的神经元中都有特异性。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受到 男性和女性的成年荷尔蒙特征不同。在具体目标2中，我们将确定顺式调节元件， 如增强子，并研究转录因子的性别差异 这些元素的占用情况。在特定目标3中，我们将测试对新性二形者的要求 转录因子在产生性别差异时的基因表达和行为。综上所述，我们的发现 将揭示早期生命中的雌激素信号如何永久性地影响成人基因表达和 归根结底，是针对性别的行为。这项工作将深入了解关键时期的瞬时事件是如何 发育时期会对成年后的大脑和行为产生重大影响。这一关键时期 永久性地影响大脑结构和功能，表明精神障碍的性别差异，如 自闭症和抑郁症可能起源于大脑的性别分化。