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A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [mouse RNA-seq]

ABSTRACT: A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [mouse RNA-seq]

PROVIDER: PRJNA810841 | ENA |

REPOSITORIES: ENA

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A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [CapHiC]

Project description:Background & Aims: A major focus of human genetics research has been to identify locally adapted alleles in global populations. In Tibetans, noncoding alleles in EPAS1 – who’s protein product HIF-2 is a key driver of the response to hypoxia – carry some of the strongest signatures of positive selection found in humans, yet their functional mechanism has never been systematically examined. Here we report the discovery of three enhancers within EPAS1, whose activity is significantly disrupted by Tibetan alleles in one or more key organs (endothelium, kidney, and heart). We further characterize one of these enhancers (ENH5) whose activity was found to be not only allele-specific, but also hypoxia-dependent in all three cell types. Deletion of this enhancer results in downregulation of EPAS1 and HIF-2 targets in acute hypoxia as well as a blunting of the transcriptional response to sustained hypoxia. In vivo deletion of the orthologous 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.

2022-11-28 | GSE197526 | GEO

A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [RNA-seq TeloHAEC]

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A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [mouse RNA-seq]

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A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [Paired ATAC-seq & RNA-seq]

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A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans

Project description:A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans

| PRJNA810836 | ENA

A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [CapHiC]

Project description:A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [CapHiC]

| PRJNA810839 | ENA

A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [RNA-seq TeloHAEC]

Project description:A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [RNA-seq TeloHAEC]

| PRJNA810840 | ENA

A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [Paired ATAC-seq & RNA-seq]

Project description:A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans [Paired ATAC-seq & RNA-seq]

| PRJNA810842 | ENA

A pleiotropic hypoxia-sensitive <i>EPAS1</i> enhancer is disrupted by adaptive alleles in Tibetans.

Project 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.

| S-EPMC9683707 | biostudies-literature

A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-28 | GSE197527 | GEO