Published November 23, 2022
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A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans
Description
In Tibetans, noncoding alleles in EPAS1—whose protein product hypoxia-inducible factor 2α (HIF-2α) drives the response to hypoxia—carry strong signatures of positive selection; however, their functional mechanism has not been systematically examined. Here, we report that high-altitude alleles disrupt the activity of four EPAS1 enhancers in one or more cell types. We further characterize one enhancer (ENH5) whose activity is both allele specific and hypoxia dependent. Deletion of ENH5 results in down-regulation of EPAS1 and HIF-2α targets in acute hypoxia and in a blunting of the transcriptional response to sustained hypoxia. Deletion of ENH5 in mice results in dysregulation of gene expression across multiple tissues. We propose that pleiotropic adaptive effects of the Tibetan alleles in EPAS1 underlie the strong selective signal at this gene.
Data availability
Data described in this paper can be found in the Supplementary Materials or in publicly available databases including the UCSC genome browser and Epigenome Roadmap. All sequencing data are deposited in the GEO accession database (www.ncbi.nlm.nih.gov/geo/); accession no. GSE197527 (HAEC ATAC-seq/RNA-seq: GSE197523; teloHAEC RNA-seq: GSE197525; Capture Hi-C: GSE197526, mouse RNA-seq: GSE197524).
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Additional details
Identifiers
- DOI
- 10.1126/sciadv.ade1942
- Other
- oai:uchicago.tind.io:10908
Funding
- National Institutes of Health
- HL119577
- National Institutes of Health
- GM007197
- National Institutes of Health
- HL07605
- National Institutes of Health
- HL142146