title: HIF-2α regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox cis regulatory element.
abstract: Low O2 tension is beneficial for human embryonic stem cell (hESC) maintenance but the mechanism of regulation is unknown. HIF-2α was found to bind directly to predicted hypoxic response elements (HREs) in the proximal promoter of OCT4, NANOG and SOX2 only in hESCs cultured under hypoxia (5% O2). This binding induced an array of histone modifications associated with gene transcription while a heterochromatic state existed at atmospheric O2. Interestingly, an enhanced euchromatic state was found when hESCs were exposed to hypoxia followed by 72 hours reoxygenation. This was sustained by HIF-2α which enhanced stemness by binding to an oct-sox cis-regulatory element in the NANOG promoter. Thus, these data have uncovered a novel role of HIF-2α as a direct regulator of key transcription factors controlling self-renewal in hESCs but also in the induction of epigenetic modifications ensuring a euchromatic conformation which enhances the regenerative potential of these cells.
authors.affiliation: Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Petruzzelli
authors.affiliation: Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Christensen
authors.affiliation: Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Parry
authors.affiliation: Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sanchez-Elsner
authors.affiliation: Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Franchesca D
authors.initials: FD
authors.lastname: Houghton
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C486780:NANOG protein, human