Sex-specific trajectories in epigenomic regulation of brain patterning

大脑模式表观基因组调控的性别特异性轨迹

• 批准号: 10610415
• 负责人: FLORA M VACCARINO
• 金额: $ 100.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610415
• 关键词: ATAC-seq; Affect; Alzheimer' s Disease; Anterior; Attention deficit hyperactivity disorder; Autopsy; Biological; Biological Markers; Brain; Cells; Clinical; Code; Collection; Data; Data Set; Development; Diagnostic; Disease; Disease Outcome; Disease susceptibility; Embryo; Enhancers; Epigenetic Process; Event; Extracellular Matrix; Female; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Enhancer Element; Genetic Risk; Gilles de la Tourette syndrome; Goals; Gonadal Steroid Hormones; Hereditary Disease; Human; Human Development; Incidence; Individual; Inherited; Intrinsic drive; Knowledge; Longitudinal Studies; Maps; Modeling; Molecular; Neurodevelopmental Disorder; Organoids; Outcome; Pathogenicity; Pattern; Peptides; Predisposition; Prevalence; Proteins; Proteome; Regulation; Regulator Genes; Regulatory Element; Research Personnel; Resolution; Risk; Risk Factors; Schizophrenia; Severities; Severity of illness; Sex Bias; Sex Differences; Shapes; Testing; Time; Tissue-Specific Gene Expression; Tissues; Untranslated RNA; Variant; Work; autism spectrum disorder; cell type; design; developmental disease; disorder risk; epigenome; epigenomics; fetal; gene network; gene product; gene regulatory network; genetic risk factor; genetic variant; genome sequencing; genome wide association study; gonad development; human fetal brain; induced pluripotent stem cell; male; multidisciplinary; novel therapeutic intervention; overexpression; proband; programs; protective factors; protein expression; risk variant; sex; sexual dimorphism; transcriptome; transcriptome sequencing; trend; virtual; whole genome

The core concept of our proposed studies is that sex-biased gene expression early in human development pattern the brain differently in males and females, and that this patterning underlies differential susceptibility of males and females to neurodevelopmental disorders. We envision that these sex differences are regulated by epigenetic programs controlling the expression of developmentally regulated genes in a sex-biased manner. We further postulate that these sex- dependent epigenetic mechanisms interact with genetic risk factors that influence risk, progression, and severity of autism sprectrum disorders (ASD) and schizophrenia (SCZ), and we will test these hypotheses in two specific aims. Aim 1 is to delineate the sex-dependent regulation of early brain development in typical individuals. Epigenetic and gene expression programs in brain organoids and postmortem fetal brains will be evaluated on multiple levels, including transcriptome, proteome, and activity of noncoding regulatory elements. The objective of this aim is to define a network of genes and their regulatory elements—primarily enhancers—that are differentially active between males and females during early brain development. Aim 2 will determine whether the sex-biased regulatory network carries an increased burden of potentially pathogenic or risk associated genetic variants in developmental disorders such as SCZ and ASD. We will query available genome sequencing and GWAS datasets of probands and typical controls to determine whether the sex-biased regulatory network are enriched for rare and common inherited disease variants. Enrichment of these variants in the sex-biased regulatory network will reveal potential mechanisms by which sex-biased gene expression affects SCZ and ASD genetic risk and trajectory. The impact of this work is seeking the first detailed understanding of early sexually dimorphic brain development. The new knowledge will constitute a fundamental advance in our understanding of normal development, and will pioneer the discovery of how disease susceptibility depends on sex-biased gene regulation in the developing brain.

我们提出的研究的核心概念是，人类早期的性别偏见基因表达 男性和女性的大脑发育模式不同，而这种模式的基础 男性和女性对神经发育障碍的易感性不同。我们设想 这些性别差异是由控制表达的表观遗传程序调节的 以性别偏向的方式调控发育的基因。我们进一步假设这些性- 依赖的表观遗传机制与影响风险的遗传风险因素相互作用， 自闭症谱系障碍 (ASD) 和精神分裂症 (SCZ) 的进展和严重程度，我们 将在两个特定目标中测试这些假设。目标 1 是描绘性别依赖性调节 典型个体的早期大脑发育。表观遗传和基因表达程序 大脑类器官和死后胎儿大脑将在多个层面进行评估，包括 转录组、蛋白质组和非编码调控元件的活性。这一目标的目的 是定义一个基因网络及其调控元件（主要是增强子） 在早期大脑发育过程中，男性和女性之间的活跃程度存在差异。目标2将 确定存在性别偏见的监管网络是否会增加潜在的负担 SCZ 和 ASD 等发育障碍的致病性或风险相关的遗传变异。 我们将查询先证者和典型对照的可用基因组测序和 GWAS 数据集 确定性别偏见的监管网络是否丰富了罕见和常见的 遗传性疾病变异体。这些变异在性别偏向的监管网络中的丰富将 揭示性别偏见基因表达影响 SCZ 和 ASD 遗传的潜在机制 风险和轨迹。这项工作的影响是寻求早期的详细了解 性别二态性大脑发育。新知识将构成根本性进步 加深我们对正常发育的理解，并将开创疾病如何发生的发现 易感性取决于发育中大脑中性别偏向的基因调控。