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Nat Genet. 2019 Aug;51(8):1252-1262. doi: 10.1038/s41588-019-0472-1. Epub 2019 Jul 31.

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

Song M1,2, Yang X1, Ren X1, Maliskova L1, Li B1, Jones IR1, Wang C3, Jacob F4,5,6, Wu K7, Traglia M8, Tam TW1, Jamieson K1, Lu SY9,10,11, Ming GL4,5,12,13,14, Li Y15,16,17, Yao J9,10,11, Weiss LA1,8, Dixon JR18, Judge LM7,19, Conklin BR7,20,21, Song H4,5,12,13,22, Gan L3,23,24,25, Shen Y26,27,28.

Author information

1
Institute for Human Genetics, University of California, San Francisco, CA, USA.
2
Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, CA, USA.
3
Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.
4
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, USA.
8
Department of Psychiatry, University of California, San Francisco, CA, USA.
9
Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
10
State Key Laboratory of Membrane Biology, Tsinghua University, Beijing, China.
11
IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.
12
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
13
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA.
14
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
15
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
16
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
17
Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA.
18
Salk Institute for Biological Studies, La Jolla, CA, USA.
19
Department of Pediatrics, University of California, San Francisco, CA, USA.
20
Department of Medicine, University of California, San Francisco, CA, USA.
21
Department of Ophthalmology, University of California, San Francisco, CA, USA.
22
Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
23
Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY, USA.
24
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
25
Department of Neurology, University of California, San Francisco, CA, USA.
26
Institute for Human Genetics, University of California, San Francisco, CA, USA. yin.shen@ucsf.edu.
27
Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, CA, USA. yin.shen@ucsf.edu.
28
Department of Neurology, University of California, San Francisco, CA, USA. yin.shen@ucsf.edu.

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.

PMID:
31367015
PMCID:
PMC6677164
[Available on 2020-01-31]
DOI:
10.1038/s41588-019-0472-1

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