A promoter interaction map for cardiovascular disease genetics

Lindsey E. Montefiori; Debora R. Sobreira; Noboru J. Sakabe; Ivy Aneas; Amelia C. Joslin; Grace T. Hansen; Grazyna Bozek; Ivan P. Moskowitz; Elizabeth M. McNally; Marcelo A. Nóbrega

doi:10.7554/eLife.35788

A promoter interaction map for cardiovascular disease genetics

Lindsey E. Montefiori, Debora R. Sobreira, Noboru J. Sakabe, Ivy Aneas, Amelia C. Joslin, Grace T. Hansen, Grazyna Bozek, Ivan P. Moskowitz, Elizabeth M. McNally, Marcelo A. Nóbrega^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

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 1999 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.

Original language	English (US)
Article number	e35788
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.35788
State	Published - Jul 10 2018

Funding

We kindly thank the laboratory of Yoav Gilad for providing the iPSC line and assisting with the cardi-omyocyte differentiation protocol, and Dr. Kohta Ikegami for assistance with the ChIP-seq protocol. This work was supported by NIH grants HL123857 (MAN), HL119967 (MAN), HL118758 (MAN), HL128075 (MAN and EMM), T32GMOO7197 (LEM), American Heart Association Pre-doctoral award 17PRE33410726 (LEM), HL137307 (LEM).

ASJC Scopus subject areas

General Immunology and Microbiology
General Biochemistry, Genetics and Molecular Biology
General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.7554/eLife.35788

Cite this

@article{e153c13cd4e849589fe7db56468ff150,

title = "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 1999 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.",

author = "Montefiori, {Lindsey E.} and Sobreira, {Debora R.} and Sakabe, {Noboru J.} and Ivy Aneas and Joslin, {Amelia C.} and Hansen, {Grace T.} and Grazyna Bozek and Moskowitz, {Ivan P.} and McNally, {Elizabeth M.} and N{\'o}brega, {Marcelo A.}",

note = "Publisher Copyright: {\textcopyright} Montefiori et al.",

year = "2018",

month = jul,

day = "10",

doi = "10.7554/eLife.35788",

language = "English (US)",

volume = "7",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

TY - JOUR

T1 - A promoter interaction map for cardiovascular disease genetics

AU - Montefiori, Lindsey E.

AU - Sobreira, Debora R.

AU - Sakabe, Noboru J.

AU - Aneas, Ivy

AU - Joslin, Amelia C.

AU - Hansen, Grace T.

AU - Bozek, Grazyna

AU - Moskowitz, Ivan P.

AU - McNally, Elizabeth M.

AU - Nóbrega, Marcelo A.

PY - 2018/7/10

Y1 - 2018/7/10

N2 - 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 1999 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.

AB - 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 1999 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.

UR - http://www.scopus.com/inward/record.url?scp=85052065410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052065410&partnerID=8YFLogxK

U2 - 10.7554/eLife.35788

DO - 10.7554/eLife.35788

M3 - Article

C2 - 29988018

AN - SCOPUS:85052065410

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

M1 - e35788

ER -

A promoter interaction map for cardiovascular disease genetics

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this