| Autor: |
Michael Song, Jun Yao, Kirsty Jamieson, Li Gan, Chao Wang, Yin Shen, Bingkun Li, Jesse R. Dixon, Si-Yao Lu, Kenneth Wu, Guo Li Ming, Fadi Jacob, Michela Traglia, Hongjun Song, Lenka Maliskova, Ian R. Jones, Bruce R. Conklin, Xiaoyu Yang, Tse Wai Tam, Luke M. Judge, Lauren A. Weiss, Xingjie Ren |
| Rok vydání: |
2018 |
| Předmět: |
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| Popis: |
Mutations in gene regulatory elements have been associated with a wide range of complex 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 using promoter capture Hi-C (pcHi-C), open chromatin regions using ATAC-seq, and transcriptomes using RNA-seq in four functionally distinct neural cell types: iPSC-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus (DG)-like neurons, and primary astrocytes. We identify hundreds of thousands of long-rangecisinteractions between promoters and distal promoter-interacting regions (PIRs), enabling us to link regulatory elements to their target genes and reveal putative pathways that are dysregulated in disease. We validate several novel PIRs using CRISPR techniques in human excitatory neurons, demonstrating thatCDK5RAP3, STRAP, andDRD2are transcriptionally regulated by physically linked enhancers. Finally, we show that physical chromatin interactions mediate genetic interactions in autism spectrum disorder (ASD). Our study illustrates how characterizing the 3D epigenome elucidates novel regulatory relationships in the central nervous system (CNS), shedding light on previously unknown functions for noncoding variants in complex neurological disorders. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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