TY - JOUR
T1 - Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes
AU - Ward, Michelle C.
AU - Banovich, Nicholas E.
AU - Sarkar, Abhishek
AU - Stephens, Matthew
AU - Gilad, Yoav
N1 - Funding Information:
We thank Kristen Patterson and Amy Mitrano for experimental assistance, David Knowles and Benjamin Strober for preliminary data exploration, all members of the Gilad lab and Luis Barreiro for helpful discussions, and Natalia Gonzales for comments on the manuscript. We thank the Genomics Core Facility at the University of Chicago for sequencing the libraries and processing the DNA methylation arrays. We thank The Genotype-Tissue Expression (GTEx) Project, supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS, for providing data. The data used for the analyses described in this manuscript were obtained from the GTEx portal v8 on December 30th 2020. We thank the ENCODE Consortium and the Bernstein Lab at Broad for generating and making the histone mark ChIP-seq data available.
Publisher Copyright:
© Ward et al.
PY - 2021/2
Y1 - 2021/2
N2 - One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia, and short-or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.
AB - One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia, and short-or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.
UR - http://www.scopus.com/inward/record.url?scp=85101956338&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101956338&partnerID=8YFLogxK
U2 - 10.7554/eLife.57345
DO - 10.7554/eLife.57345
M3 - Article
C2 - 33554857
AN - SCOPUS:85101956338
SN - 2050-084X
VL - 10
SP - 1
EP - 33
JO - eLife
JF - eLife
M1 - e57345
ER -