TY - JOUR T1 - <em>cis</em>-Regulatory Chromatin Contacts in Neural Cells Reveal Contributions of Genetic Variants to Complex Neurological Disorders JF - bioRxiv DO - 10.1101/494450 SP - 494450 AU - Michael Song AU - Xiaoyu Yang AU - Xingjie Ren AU - Chao Wang AU - Fadi Jacob AU - Kenneth Wu AU - Michela Traglia AU - Bingkun Li AU - Lenka Maliskova AU - Ian Jones AU - Kirsty Jamieson AU - Si-Yao Lu AU - Tse Wai Tam AU - Guo-Li Ming AU - Jesse Dixon AU - Lauren A. Weiss AU - Jun Yao AU - Luke Judge AU - Bruce Conklin AU - Hongjun Song AU - Li Gan AU - Yin Shen Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/13/494450.abstract N2 - Mutations in gene regulatory elements have been associated with a wide range of neurological disorders. However, due to their inherent cell type specificity and difficulties in characterizing their regulatory targets, our ability to identify causal genetic variants has remained limited. To address these constraints, we perform integrative analysis of chromatin interactions (promoter capture Hi-C), open chromatin regions (ATAC-seq), and transcriptomes (RNA-seq) in four functionally distinct cell types associated with neurological disorders: iPSC-induced cortical excitatory neurons, hippocampal dentate gyrus (DG)-like neurons, lower motor neurons, and human primary fetal astrocytes. We identify hundreds of thousands of cell type-specific, long-range cis interactions between promoters and distal promoter-interacting regions (PIRs), enabling us to link regulatory elements to their target genes and identify putative pathways that are dysregulated in disease. Finally, we perform validation of novel PIRs linked to neuronal function using CRISPR/Cas9 editing in human neurons, demonstrating downregulation of CDK5RAP3, STRAP, and DRD2 upon knockdown of their corresponding enhancers. Our study demonstrates how cis-regulatory interactions in human neural cells can be used to elucidate the contribution of genetic variants to complex neurological disorders. ER -