Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements
- PMID: 28945252
- PMCID: PMC5805393
- DOI: 10.1038/ng.3963
Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements
Abstract
The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.
Conflict of interest statement
The authors declare competing financial interests: details are available in the online version of the paper.
Figures






Similar articles
-
Enhancers looping to target genes.Nat Genet. 2017 Oct 27;49(11):1564-1565. doi: 10.1038/ng.3982. Nat Genet. 2017. PMID: 29074944
-
Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders.J Invest Dermatol. 2019 Mar;139(3):605-614. doi: 10.1016/j.jid.2018.09.011. Epub 2018 Oct 10. J Invest Dermatol. 2019. PMID: 30315781
-
Mutations in the noncoding genome.Curr Opin Pediatr. 2015 Dec;27(6):659-64. doi: 10.1097/MOP.0000000000000283. Curr Opin Pediatr. 2015. PMID: 26382709 Free PMC article. Review.
-
Discovery of stimulation-responsive immune enhancers with CRISPR activation.Nature. 2017 Sep 7;549(7670):111-115. doi: 10.1038/nature23875. Epub 2017 Aug 30. Nature. 2017. PMID: 28854172 Free PMC article.
-
Identifying functional noncoding variants from genome-wide association studies for cardiovascular disease and related traits.Curr Opin Lipidol. 2015 Apr;26(2):120-6. doi: 10.1097/MOL.0000000000000158. Curr Opin Lipidol. 2015. PMID: 25692342 Review.
Cited by
-
Genetic association and Mendelian randomization for hypothyroidism highlight immune molecular mechanisms.iScience. 2022 Aug 20;25(9):104992. doi: 10.1016/j.isci.2022.104992. eCollection 2022 Sep 16. iScience. 2022. PMID: 36093044 Free PMC article.
-
MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data.Nat Commun. 2024 Jul 17;15(1):6027. doi: 10.1038/s41467-024-50380-3. Nat Commun. 2024. PMID: 39025865 Free PMC article.
-
Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods.Mol Cell. 2019 Jan 17;73(2):250-263.e5. doi: 10.1016/j.molcel.2018.10.039. Epub 2018 Dec 6. Mol Cell. 2019. PMID: 30527662 Free PMC article.
-
Inferring regulatory element landscapes and gene regulatory networks from integrated analysis in eight hulless barley varieties under abiotic stress.BMC Genomics. 2022 Dec 20;23(1):843. doi: 10.1186/s12864-022-09070-x. BMC Genomics. 2022. PMID: 36539685 Free PMC article.
-
High-resolution genetic mapping of putative causal interactions between regions of open chromatin.Nat Genet. 2019 Jan;51(1):128-137. doi: 10.1038/s41588-018-0278-6. Epub 2018 Nov 26. Nat Genet. 2019. PMID: 30478436 Free PMC article.
References
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials