Cavadas, Miguel A. S.Miguel A. S.CavadasMesnieres, MarionMarionMesnieresCrifo, BiancaBiancaCrifoManresa, Mario C.Mario C.ManresaSelfridge, Andrew C.Andrew C.SelfridgeScholz, Carsten C.Carsten C.ScholzCummins, Eoin P.Eoin P.CumminsCheong, AlexAlexCheongTaylor, Cormac T.Cormac T.Taylor2017-12-192017-12-192015-12-09REST mediates resolution of HIF-dependent gene expression in prolonged hypoxiahttp://hdl.handle.net/10197/9123The 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-1a expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1a 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-1a protein response and the suppression of HIF-1a mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1a promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1a mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1a- (but not HIF-2a-) dependent manner. Finally, REST promotes the resolution of HIF-1a protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1a in prolonged hypoxia, thus contributing to the resolution of the HIF-1a response.enThe final publication is available at www.springerlink.com. This work is licensed under a Creative Commons Attribution 4.0 International License.RESTHIFGene regulationTranscriptional regulatory elementsJournal Article510.1038/srep178512017-12-08https://creativecommons.org/licenses/by-nc-nd/3.0/ie/