Connecting gene regulatory mechanisms in human brain to psychiatric illness

修改项目摘要/摘要部分 在K99阶段的奖励中，我成功地接受了遗传学和生物信息学方面的培训，之后我接受了查佩尔山的北卡罗来纳州大学的终身教职。我将继续致力于这项提案的R 00阶段，该阶段旨在通过Hi-C（一种全基因组染色体构象捕获技术）描述人类大脑中两个主要时期（产前和产后发育阶段）和两种主要细胞类型（神经元和非神经元）的全基因组染色质景观。在K99阶段，我们已经在人类胎儿和成人皮质中产生了高分辨率的染色质相互作用谱，并分选了神经元和非神经元（目标1）。胎儿和成人脑中染色体构象的比较显示，成人脑中的主要构象变化反映了围产期广泛的胶质细胞生成，突出了细胞类型特异性染色质结构的重要性。我们现在将利用这一全面的染色质景观分配基因的行动非编码变异，易患神经精神疾病（目的2）。非编码变体和靶基因之间的功能关系将通过使用大规模平行报告基因测定（MPRA）和CRISPR/Cas9介导的基因组编辑（Aim 3）的实验验证来询问。总的来说，这个项目的完成将揭开精神病病因学的基因组折叠原理。

Modified Project Summary/Abstract Section After a successful training in genetics and bioinformatics during the K99 phase of the award, I accepted a tenure-track faculty position at the University of North Carolina at Chapel Hill. I will keep working on the R00 phase of this proposal, which seeks to characterize the genome-wide chromatin landscape in human brains across two major epochs (prenatal and postnatal developmental stages) and two major cell types (neurons and non-neurons) via Hi-C, a genome-wide chromosome conformation capture technology. During the K99 phase, we have generated high-resolution chromatin interaction profiles in human fetal and adult cortices and sorted neurons and non-neurons (Aim 1). Comparison of chromosome conformation in fetal and adult brain has revealed that the major conformation change in adult brain reflects extensive gliogenesis in the perinatal period, highlighting the importance of cell-type specific chromatin architecture. We will now employ this comprehensive chromatin landscape to assign genes of action to non-coding variants that predispose to neuropsychiatric illnesses (Aim 2). The functional relationship between non-coding variants and target genes will be interrogated by experimental validation using massive parallel reporter assays (MPRA) and CRISPR/Cas9-mediated genome editing (Aim 3). Collectively, completion of this project will unravel the folding principles of the genome underlying the psychiatric etiology.