title: Capture-C reveals preformed chromatin interactions between HIF-binding sites and distant promoters.
abstract: Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia. Pan-genomic analyses, using chromatin immunoprecipitation and transcript profiling, have revealed large numbers of HIF-binding sites that are generally associated with hypoxia-inducible transcripts, even over long chromosomal distances. However, these studies do not define the specific targets of HIF-binding sites and do not reveal how induction of HIF affects chromatin conformation over distantly connected functional elements. To address these questions, we deployed a recently developed chromosome conformation assay that enables simultaneous high-resolution analyses from multiple viewpoints. These assays defined specific long-range interactions between intergenic HIF-binding regions and one or more promoters of hypoxia-inducible genes, revealing the existence of multiple enhancer-promoter, promoter-enhancer, and enhancer-enhancer interactions. However, neither short-term activation of HIF by hypoxia, nor long-term stabilization of HIF in von Hippel-Lindau (VHL)-defective cells greatly alters these interactions, indicating that at least under these conditions, HIF can operate on preexisting patterns of chromatin-chromatin interactions that define potential transcriptional targets and permit rapid gene activation by hypoxic stress.
authors: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors: James L
authors: JL
authors: Platt
authors: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors: Rafik
authors: R
authors: Salama
authors: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors: James
authors: J
authors: Smythies
authors: Department of Biochemistry, Faculty of Science, Center of Innovation in Personalized Medicine King Fahd Center for Medical Research King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Hani
authors: H
authors: Choudhry
authors: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine University of Oxford, Oxford, UK.
authors: James Oj
authors: JO
authors: Davies
authors: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine University of Oxford, Oxford, UK.
authors: Jim R
authors: JR
authors: Hughes
authors: Target Discovery Institute, University of Oxford, Oxford, UK drmole@well.ox.ac.uk Peter.Ratcliffe@ndm.ox.ac.uk.
authors: Peter J
authors: PJ
authors: Ratcliffe
authors: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK drmole@well.ox.ac.uk Peter.Ratcliffe@ndm.ox.ac.uk.
authors: David R
authors: 0000-0002-0984-300X
authors: DR
authors: Mole
mesh_terms: D000465:Algorithms; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006019:Glycolysis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D051793:Hypoxia-Inducible Factor 1; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: 
  HIF
  ; Capture‐C; Hypoxia; chromatin; cis‐interaction