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.
Highlights
Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia
The findings revealed that most intergenic regions that bind HIF in hypoxic cells bear the marks of active enhancers in normoxic cells and that cis-interactions between these sites and hypoxia responsive promoters are already established, with few changes occurring during induction of the HIF response by hypoxia
To investigate HIF-binding sites that are distant from annotated gene promoters or transcribed regions of the genome [7], we first defined whether these distal sites carry histone modifications consistent with enhancers rather than unidentified promoters
Summary
Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia. They demonstrated cis-acting chromatin interactions from HIF-binding regions to multiple types of DNA element, including both the promoters of hypoxia-inducible genes and other distant elements over distances of up to 250 kb.
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