| First Author | Gray OA | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 47 | Pages | eade1942 |
| PubMed ID | 36417539 | Mgi Jnum | J:351049 |
| Mgi Id | MGI:7410458 | Doi | 10.1126/sciadv.ade1942 |
| Citation | Gray OA, et al. (2022) A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans. Sci Adv 8(47):eade1942 |
| abstractText | In Tibetans, noncoding alleles in EPAS1-whose protein product hypoxia-inducible factor 2alpha (HIF-2alpha) 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-2alpha 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. |
