Abstract
Hypoxia‐inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF‐α isoforms, HIF‐1α and HIF‐2α, are progressively stabilized in response to hypoxia and form heterodimers with HIF‐1β to activate a broad range of transcriptional responses. Here, we report on the pan‐genomic distribution of isoform‐specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF‐α isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell‐type‐specific sites across the genome, with little evidence of redistribution under any of the conditions examined. Marked biases towards promoter‐proximal binding of HIF‐1 and promoter‐distant binding of HIF‐2 were observed under all conditions and were consistent in multiple cell type. The findings imply that each HIF isoform has an inherent property that determines its binding distribution across the genome, which might be exploited to therapeutically target the specific transcriptional output of each isoform independently.
Highlights
Transcriptional reprogramming of hypoxic cells enables a wide range of adaptive cellular responses that vary with the site, severity and duration of hypoxic stress [1,2,3,4,5]
We first explored the concordance between endogenous hypoxia-inducible factor (HIF)-a and HIF-1b binding in a range of settings
To display the level of HIF-1b binding across HIF-a sites, the sites were ranked according to HIF-1b signal intensity, and heatmaps of HIF-a and HIF-1b signal intensity, centred on the summit of each peak Æ 5 kb, were plotted (Fig 1A–D)
Summary
Transcriptional reprogramming of hypoxic cells enables a wide range of adaptive cellular responses that vary with the site, severity and duration of hypoxic stress [1,2,3,4,5]. A large body of work has implicated hypoxia-inducible factor (HIF) as the central transcriptional mediator of these responses [2]. The HIF transcriptional cascade has the potential to induce both adaptive and maladaptive responses [2], so that in many situations, the ideal approach would be one of the selective manipulations of specific components of the response. Hypoxia-inducible factor comprises an a/b heterodimer of basic helix–loop–helix PAS proteins [2,10]. HIF-a polypeptides escape destruction and are able to associate with HIF-b to drive transcriptional responses [4]. An increasing body of data suggests that HIF-1 and HIF-2 heterodimers have distinct physiological functions and roles in disease [13,14]. Following the constitutive activation of both isoforms in VHL-defective kidney cancer, several pieces of evidence point to an oncogenic role for HIF-2a, whereas HIF-1a appears to manifest opposing tumour suppressor properties [15,16,17]
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