Connecting gene regulatory mechanisms in human brain to psychiatric illness

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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.