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Genome-wide mapping of HIF-2α binding under normoxia in human bronchial epithelial cells (BEAS-2B)

ABSTRACT: Growing number of cancer (stem) cells and stem cells were described to accommodate constituent active HIF-2α under normoxia. Previous study of hypoxia effect may have obscured some of normoxic HIF-2α functions as hypoxia inducible features. Our interest in study of protective potential of HIFs in lung cells led us to discover pseudohypoxia functions of HIF-2α under normoxia in human bronchial epithelial cells which exhibit pluripotency related markers and features. Our study provided perspective to pseudohypoxia functions of HIF-2α via enrichment of de novo motifs. In addition to the C-TAD, the N-TAD of HIF-2α was found to contribute to targeting on these non-canonical loci. Further elucidation of pseudohypoxia mechanism could resolve its implication of malignancy or pluripotency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81635 | GEO | 2016/07/06

SECONDARY ACCESSION(S): PRJNA322171

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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Genome-wide mapping of HIF-2α binding under normoxia in human bronchial epithelial cells (BEAS-2B)

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