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.
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HIF , Capture‐C, Hypoxia, chromatin, cis‐interaction, Algorithms, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, Cluster Analysis, Computational Biology, Enhancer Elements, Genetic, Gene Expression Regulation, Glycolysis, High-Throughput Nucleotide Sequencing, Humans, Hypoxia-Inducible Factor 1, Organ Specificity, Promoter Regions, Genetic, Protein Binding, Transcriptional Activation