Genome-wide analysis of HIF-2α chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions

Meng Chang Lee, Hsin Ju Huang, Tzu Hao Chang, Hsieh Chou Huang, Shen Yuan Hsieh, Yi Siou Chen, Wei Yuan Chou, Chiao Hsi Chiang, Ching Huang Lai, Chia Yang Shiau

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Abstract

Constitutive functional HIF-2α was recently identified in cancer and stem cell lines under normoxia. In this study, BEAS-2B, a bronchial epithelial cell line, was shown to constitutively express active HIF-2α under normoxia and exhibit markers of pluripotency including Oct-4, Nanog, and sphere formation. Oct-4 expression was reduced after knockdown of HIF-2α under normoxia. Global enrichment analysis of HIF-2α demonstrated the diverse functions of HIF-2α under normoxia. Bioinformatics analysis of the enriched loci revealed an enhancer role of HIF-2α binding sites, involvement of HIF-2α interacting proteins, and enriched de novo motifs which suggest the diverse role of HIF-2α in pseudohypoxia. The low ratio of the discovered loci overlapping with those revealed in cancer cell lines 786-O (16.1%) and MCF-7 (15.9%) under hypoxia indicated a prevailing non-canonical mechanism. Hypoxia had positive, marginal or adverse effects on the enrichment of the selected loci in ChIP-PCR assays. Deletion of the N-terminal activation domain (N-TAD) of HIF-2α disrupted the reporting activity of two of the loci annotated to ELN and ANKRD31. Hypoxia incurring abundance variation of HIF-2α may misrepresent the N-TAD functions as canonical hypoxia inducible features via C-TAD activation. Elucidation of the pseudohypoxia functions of constitutive HIF-2α is useful for resolving its role in malignancy and pluripotency.

Original languageEnglish
Article number29311
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Jul 4 2016

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    Lee, M. C., Huang, H. J., Chang, T. H., Huang, H. C., Hsieh, S. Y., Chen, Y. S., Chou, W. Y., Chiang, C. H., Lai, C. H., & Shiau, C. Y. (2016). Genome-wide analysis of HIF-2α chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions. Scientific Reports, 6, [29311]. https://doi.org/10.1038/srep29311