Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes
2019-07-31;51(8):1252-1262.
- 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.
- Consortium data used in this publication
- GSE113480--Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes [ATAC-seq]; GSE113481--Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes [PCHiC]; GSE113482--Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes [RNA-Seq]; GSE126211--Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes [CUT&RUN] All datasets used in this study (pcHi-C, ATAC-seq, RNA-seq, CUT&RUN, and chromosome-wide SNP phasing data) are available at the Gene Expression Omnibus under the accession number GSE113483. Open chromatin peaks and gene expression results for each cell type are also available on Zenodo through the following link: https://zenodo.org/record/3243977 Data can be visualized on the WashU Epigenome Browser using the session bundle ID (session ID in parentheses): 6e375740-8e71-11e9-be37-cb77c4bbb5fc (brain_ pchic_nature_genetics_00). Alternatively, the data can also be visualized on the legacy WashU Epigenome Browser (session ID in parentheses): http://epigenomegateway.wustl.edu/legacy/?g enome=g19&session=8OCs2rkpEA (brain_pchic_nature_genetics_00). Tracks include ATAC-seq signal, chromatin interactions with score ≥5 and RNA-seq plus and minus strand signal for each cell type. HindIII fragments, in vivo-validated enhancer elements, GENCODE 19 genes and GWAS SNPs are also displayed.