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

Michael Song; Xiaoyu Yang; Xingjie Ren; Lenka Maliskova; Bingkun Li; Ian R Jones; Chao Wang; Fadi Jacob; Kenneth Wu; Michela Traglia; Tsz Wai Tam; Kirsty Jamieson; Si-Yao Lu; Guo-Li Ming; Yun Li; Jun Yao; Lauren A Weiss; Jesse R Dixon; Luke M Judge; Bruce R Conklin; Hongjun Song; Li Gan; Yin Shen

doi:10.1038/s41588-019-0472-1

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

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

Authors

Michael Song^{1

2}, Xiaoyu Yang¹, Xingjie Ren¹, Lenka Maliskova¹, Bingkun Li¹, Ian R Jones¹, Chao Wang³, Fadi Jacob^{4

5

6}, Kenneth Wu⁷, Michela Traglia⁸, Tsz Wai Tam¹, Kirsty Jamieson¹, Si-Yao Lu^{9

10

11}, Guo-Li Ming^{4

5

12

13

14}, Yun Li^{15

16

17}, Jun Yao^{9

10

11}, Lauren A Weiss^{1

8}, Jesse R Dixon¹⁸, Luke M Judge^{7

19}, Bruce R Conklin^{7

20

21}, Hongjun Song^{4

5

12

13

22}, Li Gan^{3

23

24

25}, Yin Shen^{26

27

28}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Lineage / genetics*
Chromatin / genetics*
Chromosome Mapping
Clustered Regularly Interspaced Short Palindromic Repeats
Enhancer Elements, Genetic*
Gene Editing
Gene Expression Regulation*
Genetic Markers*
Genome, Human
Genome-Wide Association Study
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Infant
Male
Mental Disorders / genetics*
Neurons / cytology
Neurons / metabolism*
Polymorphism, Single Nucleotide
Promoter Regions, Genetic*

Substances

Chromatin
Genetic Markers

Abstract

Publication types

MeSH terms

Substances

Grants and funding