title: REST is a hypoxia-responsive transcriptional repressor.
abstract: 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.
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 Ciência, 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: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Ciara E
authors.initials: CE
authors.lastname: Keogh
authors.affiliation: Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Fabian
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: Institute of Physiology and Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.|Diabetes Complications Research Centre, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nolan
authors.affiliation: Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
authors.forename: Liliane M A
authors.initials: LM
authors.lastname: Rocha
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Ulster, Coleraine, Co. Londonderry, BT52 1SA, Northern Ireland, UK.
authors.forename: Murtaza M
authors.initials: MM
authors.lastname: Tambuwala
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Brown
authors.affiliation: Neurotherapeutics Research Group, UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Anita
authors.initials: A
authors.lastname: Wdowicz
authors.affiliation: Neurotherapeutics Research Group, UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Danielle
authors.initials: D
authors.lastname: Corbett
authors.affiliation: Neurotherapeutics Research Group, UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Murphy
authors.affiliation: Diabetes Complications Research Centre, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
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.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
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
mesh_terms: D015687:Cell Hypoxia; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D017423:Sequence Analysis, RNA / Q000379:methods*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor