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

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Title: REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia
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.
Permanent link: http://hdl.handle.net/10197/9123
Date: 9-Dec-2015
Abstract: 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-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.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Springer Nature
Journal: REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia
Volume: 5
Keywords: RESTHIFGene regulationTranscriptional regulatory elements
DOI: 10.1038/srep17851
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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