title: REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia.
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-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.
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.|Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.|Instituto Gulbenkian de Ciencia, Rua da Quinta Grande, 2780-156 Oeiras, Portugal.
authors.forename: Miguel A S
authors.initials: MA
authors.lastname: Cavadas
authors.affiliation: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Marion
authors.initials: M
authors.lastname: Mesnieres
authors.affiliation: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Bianca
authors.initials: B
authors.lastname: Crifo
authors.affiliation: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Mario C
authors.initials: MC
authors.lastname: Manresa
authors.affiliation: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Selfridge
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.|Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.|Institute of Physiology and Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Carsten C
authors.initials: CC
authors.lastname: Scholz
authors.affiliation: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.|Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.|Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Cheong
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.|Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D000099229:RE1-Silencing Transcription Factor
chemical_list: D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; D010100:Oxygen; D012333:RNA, Messenger; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor