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Manresa, Mario C.
Preferred name
Manresa, Mario C.
Official Name
Manresa, Mario C.
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Now showing 1 - 2 of 2
- PublicationREST mediates resolution of HIF-dependent gene expression in prolonged hypoxia(Springer Nature, 2015-12-09)
; ; ; ; ; ; ; ; 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.234Scopus© Citations 49 - PublicationREST is a hypoxia-responsive transcriptional repressor(Springer Nature, 2016-08-17)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.288Scopus© Citations 46