HIF-2α regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox Cis regulatory element

• Main Authors: Petruzzelli, Raffaella (Author), Christensen, David R. (Author), Parry, Kate L. (Author), Sanchez-Elsner, Tilman (Author), Houghton, Franchesca D. (Author)
• Format: Article
• Language: English
• Published: 2014-10-01.
• Subjects: Article
• Online Access: Get fulltext

 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.