REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

• Published in: Scientific reports 2015-12, Vol.5 (1), p.17851-17851, Article 17851
• Main Authors: Cavadas, Miguel A. S., Mesnieres, Marion, Crifo, Bianca, Manresa, Mario C., Selfridge, Andrew C., Scholz, Carsten C., Cummins, Eoin P., Cheong, Alex, Taylor, Cormac T.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 38; 38/15; 38/44; 631/208/200; 631/337/572/2102; Base Sequence; Binding Sites; Computational Biology; Feedback; Gene expression; Gene Expression Regulation; Gene silencing; Glucose - metabolism; Glycolysis; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Lactic acid; Lactic Acid - biosynthesis; Molecular Sequence Data; multidisciplinary; Oxygen; Oxygen - metabolism; Promoter Regions, Genetic; Protein Binding; Proteins; Repressor Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-mediated interference; Science; Sequence Alignment; Side effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep17851

The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.