A promoter interaction map for cardiovascular disease genetics
- University of Chicago, United States
- Northwestern University, United States
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).
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Article and author information
Author details
Lindsey E Montefiori
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.
Reviewing Editor
- Job Dekker, University of Massachusetts Medical School, United States
Version history
- Received: February 20, 2018
- Accepted: June 21, 2018
- Accepted Manuscript published: July 10, 2018 (version 1)
- Version of Record published: July 19, 2018 (version 2)
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.
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A promoter interaction map for cardiovascular disease genetics
eLife 7:e35788.
https://doi.org/10.7554/eLife.35788
