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

基本信息

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
项目类别：
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&apos 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

项目摘要

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偏置基因表达发展模式的大脑在男性和女性中的大脑不同，并且这种模式的基础男性和女性对神经发育障碍的差异敏感性。我们设想这些性别差异受控制的表观遗传程序的调节以性别偏见的方式开发了受调节的基因。我们进一步假设这些性别 - 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，自闭症传播疾病（ASD）和精神分裂症（SCZ）的进展和严重程度，我们将以两个具体目标来检验这些假设。目标1是描述性别依赖性法规典型个体的早期大脑发展。表观遗传和基因表达程序将在包括不编码调节元件的转录组，蛋白质组和活性。这个目标的目的是定义一个基因网络及其调节元素（主要增强子）早期大脑发育期间，男性和女性之间有差异性活跃。 AIM 2意志确定性别偏见的监管网络是否会增加潜在的燃烧病原或风险与SCZ和ASD等疾病的遗传变异有关。我们将查询可用的基因组测序以及问题和典型控制的GWAS数据集确定性别偏见的监管网络是否富含稀有和常见继承的疾病变体。在性偏见的监管网络中这些变体的丰富将揭示了性偏见的基因表达影响SCZ和ASD通用的潜在机制风险和轨迹。这项工作的影响是寻求对早期的第一个详细理解性二态性脑发育。新知识将构成基本进步在我们对正常发展的理解中，并将开创发现疾病的发现易感性取决于发育中的大脑中的性偏见基因调节。