Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes
- University of Chicago, United States
Abstract
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.
Data availability
Sequencing data have been deposited in GEO under accession codesGSE144426
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Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytesNCBI Gene Expression Omnibus, GSE144426.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (HL092206)
- Yoav Gilad
EMBO Long-Term Fellowship (ALTF 751-2014)
- Michelle C Ward
National Institute on Aging (F31 AG044948)
- Nicholas E Banovich
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Ward 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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Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes
eLife 10:e57345.
https://doi.org/10.7554/eLife.57345
Further reading
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Genes are often regulated by multiple enhancers. It is poorly understood how the individual enhancer activities are combined to control promoter activity. Anecdotal evidence has shown that enhancers can combine sub-additively, additively, synergistically, or redundantly. However, it is not clear which of these modes are more frequent in mammalian genomes. Here, we systematically tested how pairs of enhancers activate promoters using a three-way combinatorial reporter assay in mouse embryonic stem cells. By assaying about 69,000 enhancer-enhancer-promoter combinations we found that enhancer pairs generally combine near-additively. This behaviour was conserved across seven developmental promoters tested. Surprisingly, these promoters scale the enhancer signals in a non-linear manner that depends on promoter strength. A housekeeping promoter showed an overall different response to enhancer pairs, and a smaller dynamic range. Thus, our data indicate that enhancers mostly act additively, but promoters transform their collective effect non-linearly.
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