Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

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

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Michelle C Ward

    Medicine, University of Chicago, Chicago, United States
    For correspondence
    miward@utmb.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1485-320X
  2. Nicholas E Banovich

    Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Abhishek Sarkar

    Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew Stephens

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yoav Gilad

    Department of Medicine, University of Chicago, Chicago, United States
    For correspondence
    gilad@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8284-8926

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.

Reviewing Editor

  1. Oliver Stegle, European Molecular Biology Laboratory, European Bioinformatics Institute, United Kingdom

Version history

  1. Received: March 28, 2020
  2. Accepted: February 6, 2021
  3. Accepted Manuscript published: February 8, 2021 (version 1)
  4. Version of Record published: February 25, 2021 (version 2)

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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  1. Michelle C Ward
  2. Nicholas E Banovich
  3. Abhishek Sarkar
  4. Matthew Stephens
  5. Yoav Gilad
(2021)
Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes
eLife 10:e57345.
https://doi.org/10.7554/eLife.57345

Share this article

https://doi.org/10.7554/eLife.57345

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