Sex-specific trajectories in epigenomic regulation of brain patterning

我们所提出的研究的核心概念是，性别偏见的基因表达在人类早期， 男性和女性的大脑发育模式不同，这种模式构成了 男性和女性对神经发育障碍的不同易感性。我们设想 这些性别差异是由表观遗传程序控制的， 以性别偏见的方式调节基因的发育。我们进一步假设这些性- 依赖性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 将在两个具体目标中检验这些假设。目的1是阐明性别依赖性调节 典型个体的早期大脑发育。表观遗传学和基因表达程序 脑类器官和死后胎脑将在多个层面上进行评估，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 是定义一个基因及其调控元件的网络，主要是增强子， 在大脑发育早期，男性和女性的大脑活动有差异。目标2将 确定有性别偏见的监管网络是否增加了潜在的负担 致病性或风险相关的遗传变异的发育障碍，如SCZ和ASD。 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 以确定是否性别偏见的调节网络是丰富的罕见和常见的 遗传性疾病变异在性别偏见的调控网络中丰富这些变异将 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第一个详细了解早期 大脑发育的性别二态性新的知识将构成一个根本性的进步 在我们对正常发育的理解中， 易感性取决于发育中的大脑中性别偏向的基因调控。

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.