A promoter interaction map for cardiovascular disease genetics
Abstract
Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), however most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1,999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.
Data availability
Raw and processed sequencing data are provided at ArrayExpress through accession numbers E-MTAB-6014 (Hi-C) and E-MTAB-6013 (RNA-seq).
-
Roadmap Epigenome Project-RV-H3K4me1E105-H3K4me1.narrowPeak.gz.
-
Roadmap Epigenome Project-RV-H3K27acE105-H3K27ac.narrowPeak.gz.
-
Roadmap Epigenome Project-RV-H3K27me3E105-H3K27me3.narrowPeak.gz.
-
Roadmap Epigenome Project-RA-H3K4me1E104-H3K4me1.narrowPeak.gz.
-
Roadmap Epigenome Project-RA-H3K27acE104-H3K27ac.narrowPeak.gz.
-
Roadmap Epigenome Project-RA-H3K27me3E104-H3K27me3.narrowPeak.gz.
Article and author information
Author details
Funding
National Institutes of Health (HL123857)
- Marcelo A Nóbrega
National Institutes of Health (HL119967)
- Marcelo A Nóbrega
National Institutes of Health (HL118758)
- Marcelo A Nóbrega
National Institutes of Health (HL128075)
- Elizabeth M McNally
- Marcelo A Nóbrega
National Institutes of Health (T32GMOO7197)
- Lindsey E Montefiori
American Heart Association (17PRE33410726)
- Lindsey E Montefiori
National Institutes of Health (HL137307-01)
- Lindsey E Montefiori
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Montefiori et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 10,803
- views
-
- 1,279
- downloads
-
- 130
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Citations by DOI
-
- 130
- citations for umbrella DOI https://doi.org/10.7554/eLife.35788