Epigenetic regulation of sex differences in the brain

大脑性别差异的表观遗传调控

• 批准号: 10318913
• 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/10318913
• 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.

我们的赠款申请检验了以下假设：大脑中的性别差异受到表观遗传事件的调节 在围产期关键时期。在许多脊椎动物中，包括小鼠，性别特异性神经元电路的发展 在生命的头几天内雌激素信号传导的控制下。用雌激素治疗新生儿女性 不可逆转地男性化成人社会行为和基因表达。但是，使用的分子策略 通过雌激素对大脑执行持久影响的理解很少。该提议的目的是确定 两个性二态脑区域中基因表达和染色质的性别差异。后部 基质末端（BNST）和内侧杏仁核（MEA）的床核的划分高度 在新生儿雌激素控制下发展并调节先天性的互连大脑区域 特定的社会行为，例如交配和积极进取。我们假设新生儿雌激素会产生 男性特异性染色质指出，从根本上改变了神经元的细胞身份，因此它们在 行为电路。我们将通过全基因组表达和基因表达和 在幼犬和成年人中特别表达ERα的神经元中的次数。在特定目标1中，我们将确定 BNST/MEA中的性别特定基因程序，并探索这些程序是如何急性调节的 男性和女性的不同成年荷尔蒙谱。在特定目标2中，我们将确定顺式调节元素， 例如增强子，在BNST/MEA的ERα神经元中，研究转录因子的性别差异 这些要素的占用。在特定目标3中，我们将测试新型性二态的需求 转录因子在基因表达和行为中产生性别差异。两者一起，我们的发现 将揭示早期雌激素信号如何永久影响成人基因表达和 最终，特定于性别的行为。这项工作将洞悉关键期间的短暂事件 发展期会对大脑和成年后的行为产生重大影响。这个关键时期 永久影响大脑结构和功能，表明精神疾病的性别差异，这样 作为自闭症和抑郁症，可能起源于大脑的性别分化。