A promoter interaction map for cardiovascular disease genetics

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

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

2018

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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.

Details

Title

A promoter interaction map for cardiovascular disease genetics

Author

Montefiori, Lindsey E. : University of Chicago : (https://orcid.org/0000-0003-2342-6349)
Sobreira, Debora R. : University of Chicago
Sakabe, Noboru J. : University of Chicago
Aneas, Ivy : University of Chicago
Joslin, Amelia C. : University of Chicago
Hansen, Grace T. : University of Chicago
Bozek, Grazyna : University of Chicago
Moskowitz, Ivan P. : University of Chicago : (https://orcid.org/0000-0003-0014-4963)
McNally, Elizabeth M. : Northwestern University
Nóbrega, Marcelo A. : University of Chicago : (https://orcid.org/0000-0002-0451-7846)

Content Type

Article

Published in

eLife

Keywords

capture Hi-C; cardiomyocytes; GWAS; gene regulation; cardiovascular disease

Identifier(s)

DOI: https://doi.org/10.7554/eLife.35788

Data availability statement

Raw and processed sequencing data are provided at ArrayExpress through accession numbers E-MTAB-6014 (Hi-C) and E-MTAB-6013 (RNA-seq).

The following data sets were generated:

Montefiori LE Sobreira DR Sakabe NJ Aneas I Joslin AC Hansen GT Bozek G Moskowitz IP McNally EM Nóbrega MA (2018) Capture Hi-C in iPSC and CM Publicly available at ArrayExpress (accession no. E-MTAB-6014). https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6014/

Montefiori LE Sobreira DR Sakabe NJ Aneas I Joslin AC Hansen GT Bozek GMoskowitz IP McNally EM Nóbrega MA (2018) RNA-seq in iPSC and CM Publicly available at ArrayExpress (accession no. E-MTAB-6013). https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6013/

The following previously published data sets were used:

Kundaje A (2015) Roadmap Epigenome Project - H1-H3K4me1 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E003-H3K4me1.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-H1-H3K27ac Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E003-H3K27ac.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-H1-H3K27me3 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E003-H3K27me3.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-H9-H3K4me1 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E008-H3K4me1.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-H9-H3K27ac Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E008-H3K27ac.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-H9-H3K27me3 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E008-H3K27me3.narrowPeak.gz

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Kundaje A (2015) Roadmap Epigenome Project-LV-H3K27ac Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E095-H3K27ac.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-LV-H3K27me3 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E095-H3K27me3.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-RV-H3K4me1 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E105-H3K4me1.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-RV-H3K27ac Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E105-H3K27ac.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-RV-H3K27me3 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E105-H3K27me3.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-RA-H3K4me1 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E104-H3K4me1.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-RA-H3K27ac Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E104-H3K27ac.narrowPeak.gz

Kundaje A (2015) Roadmap Epigenome Project-RA-H3K27me3 Open public database: Roadmap Epigenome Project. http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/E104-H3K27me3.narrowPeak.gz

ENCODE Project Consortium (2012) H1-CTCF Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE29611). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29611

ENCODE Project Consortium (2012) Human CM - CTCF Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE35583). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE35583

Bernstein BE, Stamatoyannopoulos JA Costello JF Ren B (2010) ENCODE_RNA-seq-fetal heart 1 Publicly available at the NCBI Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/sra/SRR643778/

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B (2010) ENCODE_RNA-seq-fetal heart 2 Publicly available at the NCBI Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/sra/SRR643779/

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B (2010) ENCODE_RNA-seq-H1-1 Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM438361). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM438361

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B (2010) ENCODE_RNA-seq-H1-2 Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM958737). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM958737

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B (2010) ENCODE_RNA-seq-H1-4 Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1817053). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1817053

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B (2010) ENCODE_RNA-seq-LV-1 Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010938). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1010938

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B (2010) ENCODE_RNA-seq-LV-2 Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010964). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1010964

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) 1000G_RNA-seq-LCL_1883_GM11830_1 Publicly available at ArrayExpress. ftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR356/ERR356375/ERR356375_1.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) 1000G_RNA-seq-LCL_1883_GM11894_1 Publicly available at ArrayExpress. ftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR356/ERR356368/ERR356368_1.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) 1000G_RNA-seq-LCL_1883_GM12043_1 Publicly available at ArrayExpress. ftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR356/ERR356365/ERR356365_1.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) 1000G_RNA-seq-LCL_1883_GM12878_1 Publicly available at ArrayExpress. ftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR356/ERR356372/ERR356372_2.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2012) ENCODE_RNA-seq-LCL_encode_1 Publicly available at ArrayExpress. https://www.encodeproject.org/files/ENCFF000CXI/@@download/ENCFF000CXI.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2012) ENCODE_RNA-seq-LCL_encode_2 Publicly available at ArrayExpress. https://www.encodeproject.org/files/ENCFF000CXH/@@download/ENCFF000CXH.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) GEUVADIS_RNA-seq-LCL_geuvadis_1 Publicly available at ArrayExpress. ftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR187/ERR187488/ERR187488.fastq.gz

Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli AMigliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis N, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) GEUVADIS_RNA-seq-LCL_geuvadis_2 Publicly available at ArrayExpress. ftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR187/ERR187490/ERR187490.fastq.gz

Funding Information

National Institutes of Health, HL123857
National Institutes of Health, HL119967
National Institutes of Health, HL118758
National Institutes of Health, HL128075
National Institutes of Health, T32GMOO7197
American Heart Association, 17PRE33410726
National Institutes of Health, National Institutes of Health

Publication Date

2018-07-10

Language

English

Copyright Statement

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Licensing

CC BY

Record Appears in

Biological Sciences Division > Human Genetics
Biological Sciences Division > Pediatrics
Biological Sciences Division > Pathology
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Record Created

2023-11-28

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