A generally conserved response to hypoxia in iPSC-derived cardiomyocytes from humans and chimpanzees

Abstract
Data availability
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Abstract

Despite anatomical similarities, there are differences in susceptibility to cardiovascular disease (CVD) between primates; humans are prone to myocardial ischemia, while chimpanzees are prone to myocardial fibrosis. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) allow for direct inter-species comparisons of the gene regulatory response to CVD-relevant perturbations such as oxygen deprivation, a consequence of ischemia. To gain insight into the evolution of disease susceptibility, we characterized gene expression levels in iPSC-CMs in humans and chimpanzees, before and after hypoxia and re-oxygenation. The transcriptional response to hypoxia is generally conserved across species, yet we were able to identify hundreds of species-specific regulatory responses including in genes previously associated with CVD. The 1,920 genes that respond to hypoxia in both species are enriched for loss-of-function intolerant genes; but are depleted for expression quantitative trait loci and cardiovascular-related genes. Our results indicate that response to hypoxic stress is highly conserved in humans and chimpanzees.

Data availability

Sequencing data have been deposited in GEO under accession code GSE117192

The following data sets were generated

1. Ward M
(2018) Inter-species differences in response to hypoxia in iPSC-derived cardiomyocytes from humans and chimpanzees
NCBI Gene Expression Omnibus, GSE117192.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE117192

The following previously published data sets were used

1. GTEx consortium
(2018) GTEx v7
Genotype-Tissue Expression Project.

http://www.gtexportal.org
1. Lek & ExAC
(2016) Loss of function intolerant genes
https://doi.org/10.1038/nature19057.

https://www.nature.com/articles/nature19057
1. Cardiovascular Gene Ontology Annotation Initiative
(2015) BHF-UCL gene association file
BHF-UCL gene association file.

ftp://ftp.ebi.ac.uk/pub/databases/GO/GOA/bhf-ucl/gene_association.goa_bhf-ucl.gz
1. MacArthur
(2017) NHGRI-EBI GWAS catalog: Genes nearest to GWAS peaks
Genes nearest to GWAS peaks.

https://github.com/macarthur-lab/gene_lists/blob/master/lists/gwascatalog.tsv

Article and author information

Author details

Michelle C Ward

Department of Medicine, University of Chicago, Chicago, United States

For correspondence
mcward@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1485-320X
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.

"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

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

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.