REST is a hypoxia-responsive transcriptional repressor

  • Sci Rep. 2016 Aug 17;6:31355. doi: 10.1038/srep31355.
Miguel A S Cavadas  1  2  3 ,  Marion Mesnieres  2 ,  Bianca Crifo  2 ,  Mario C Manresa  2 ,  Andrew C Selfridge  2 ,  Ciara E Keogh  2 ,  Zsolt Fabian  2 ,  Carsten C Scholz  1  2  4 ,  Karen A Nolan  4  5 ,  Liliane M A Rocha  6 ,  Murtaza M Tambuwala  7 ,  Stuart Brown  8 ,  Anita Wdowicz  9 ,  Danielle Corbett  9 ,  Keith J Murphy  9 ,  Catherine Godson  5 ,  Eoin P Cummins  2 ,  Cormac T Taylor  1  2 ,  Alex Cheong  1  2  10
Affiliations
  • 1. Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
  • 2. Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
  • 3. Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 2780-156 Oeiras, Portugal.
  • 4. Institute of Physiology and Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
  • 5. Diabetes Complications Research Centre, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
  • 6. Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
  • 7. School of Pharmacy and Pharmaceutical Sciences, University of Ulster, Coleraine, Co. Londonderry, BT52 1SA, Northern Ireland, UK.
  • 8. Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY 10016, USA.
  • 9. Neurotherapeutics Research Group, UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
  • 10. Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
PMID: 27531581 DOI: 10.1038/srep31355
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.