Sex-specific trajectories in epigenomic regulation of brain patterning

我们提出的研究的核心概念是性别偏见基因在人类早期的表达 男性和女性的大脑发育模式不同，这种模式是 男性和女性对神经发育障碍的不同易感性。我们预见到 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发育的基因。我们进一步假设这些性行为- 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， 自闭症频谱障碍(ASD)和精神分裂症(SCZ)的进展和严重程度，我们 将在两个具体目标上检验这些假设。目标1是描述性别依赖的调节 典型个体的早期大脑发育。表观遗传和基因表达程序 脑有机物质和死后胎儿大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。这一目标的目标是 是定义一个基因网络及其调控元件--主要是增强子--它们是 在早期大脑发育过程中，男性和女性之间的差异活跃。目标2将 确定性别偏见的监管网络是否会增加潜在的 SCZ和ASD等发育障碍的致病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 为了确定性别偏见的调控网络是否丰富了稀有和常见的 遗传性疾病的变种。这些变异在性别偏见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对早期 性二相大脑发育。新知识将构成根本性的进步。 在我们了解正常发育的基础上，将率先发现疾病是如何发生的 易感性取决于发育中大脑中性别偏见的基因调控。

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.