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Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes.

TitleMapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes.
Publication TypeJournal Article
Year of Publication2019
AuthorsSong M, Yang X, Ren X, Maliskova L, Li B, Jones IR, Wang C, Jacob F, Wu K, Traglia M, Tam TWai, Jamieson K, Lu S-Y, Ming G-L, Li Y, Yao J, Weiss LA, Dixon JR, Judge LM, Conklin BR, Song H, Gan L, Shen Y
JournalNat Genet
Volume51
Issue8
Pagination1252-1262
Date Published2019 Aug
ISSN1546-1718
Abstract

Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.

DOI10.1038/s41588-019-0472-1
Alternate JournalNat. Genet.
PubMed ID31367015
PubMed Central IDPMC6677164
Grant ListR01 AG057497 / AG / NIA NIH HHS / United States
P01 NS097206 / NS / NINDS NIH HHS / United States
R35 NS097370 / NS / NINDS NIH HHS / United States
T32 GM007309 / GM / NIGMS NIH HHS / United States
R01 EY027789 / EY / NEI NIH HHS / United States
UM1 HG009402 / HG / NHGRI NIH HHS / United States
U19 MH106434 / MH / NIMH NIH HHS / United States
R01 EY028249 / EY / NEI NIH HHS / United States
R01 HL130533 / HL / NHLBI NIH HHS / United States
R01 HL135358 / HL / NHLBI NIH HHS / United States
U19 AI131130 / AI / NIAID NIH HHS / United States
R01 MH105128 / MH / NIMH NIH HHS / United States
T32 GM007175 / GM / NIGMS NIH HHS / United States
P30 EY002162 / EY / NEI NIH HHS / United States