NDM Research Building, University of Oxford, Oxford, UK.
The Francis Crick Institute, London, UK.
EMBO Rep. 2019 Jan;20(1). doi: 10.15252/embr.201846401. Epub 2018 Nov 14.
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.
缺氧诱导因子 (HIF) 是细胞对缺氧反应的主要转录调节剂。两种主要的 HIF-α 同工型，HIF-1α 和 HIF-2α，逐渐在缺氧和与 HIF-1β 形成异二聚体的反应中稳定下来，以激活广泛的转录反应。在这里，我们报告了对不同严重程度和持续时间的缺氧反应以及每种 HIF-α 同工型基因缺失的情况下，同工型特异性 HIF 结合的全基因组分布。我们的研究结果表明，尽管 DNA 中的识别序列相同，但每种 HIF 异二聚体在基因组中逐渐加载到独特的细胞类型特异性位点库中，在任何检查条件下几乎没有重新分配的证据。在所有条件下都观察到 HIF-1 的启动子近端结合和 HIF-2 的启动子远端结合的明显偏向，在多种细胞类型中也是一致的。这些发现表明，每种 HIF 同工型都具有内在的特性，决定了其在整个基因组中的结合分布，这可能被用来有针对性地治疗每种同工型的特定转录产物。
