Charting the 3D epigenome in human brain development and diseases

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Project Summary Cis-regulatory elements control Cell-type-specific gene regulation via looping with their targeting genes. Therefore, mapping the 3D chromatin interactions between promoters and cis-regulatory elements will be pivotal to understand the functions of regulatory regions. Besides, many genetic variants associated with neuropsychiatric diseases reside in the putative cis-regulatory elements. They may contribute to disease by affecting regulatory sequences function, but the exact mechanisms of how they contribute to diseases via gene regulation remain unknown. Here, we aim to make substantial advances in understanding how the 3D epigenome contributes to brain development and diseases by mapping and analyzing the dynamic changes during the human prefrontal cortex development. We will first map transcriptome, chromatin accessibility, and 3D chromatin loops in six distinct cell types from the developing prefrontal cortex and perform an integrative analysis to interrogate how chromatin interaction control gene expression and development. Second, we will integrate the 3D epigenomic datasets with medical genetics resources to gain insights into cell types, genomic loci, and biological pathways that are causal to diseases, link GWAS SNPs with their target genes. Third, to establish cell-type-specific functional links between chromatin loops and target gene expression, we will test the biological consequences of distal regulatory regions interacting with promoters in iPSC models and primary cells. Our project will reveal new insight into the biological functions of the 3D epigenome in brain development and diseases.