Reduced oxygen availability (hypoxia) can act as a signalling cue in physiological processes such as development, but also in pathological conditions such as cancer or ischaemic disease. As such, understanding how cells and organisms respond to hypoxia is of great importance. The family of transcription factors called Hypoxia Inducible Factors (HIFs) co-ordinate a transcriptional programme required for survival and adaptation to hypoxia. However, the effects of HIF on chromatin accessibility are currently unclear. Here, using genome wide mapping of chromatin accessibility via ATAC-seq, we find hypoxia induces loci specific changes in chromatin accessibility are enriched at a subset hypoxia transcriptionally responsive genes, agreeing with previous data using other models. We show for the first time that hypoxia inducible changes in chromatin accessibility across the genome are predominantly HIF dependent, rapidly reversible upon reoxygenation and partially mimicked by HIF-α stabilisation independent of molecular dioxygenase inhibition. This work demonstrates that HIF is central to chromatin accessibility alterations in hypoxia, and has implications for our understanding of gene expression regulation by hypoxia and HIF.

中文翻译：

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缺氧和 HIF 调节染色质可及性

氧气可用性降低（缺氧）可以作为生理过程（例如发育）的信号线索，也可以作为癌症或缺血性疾病等病理状况的信号线索。因此，了解细胞和生物体如何应对缺氧非常重要。称为缺氧诱导因子 (HIF) 的转录因子家族协调生存和适应缺氧所需的转录程序。然而，HIF 对染色质可及性的影响目前尚不清楚。在这里，通过 ATAC-seq 使用全基因组染色质可及性作图，我们发现缺氧诱导染色质可及性的位点特异性变化在缺氧转录反应基因子集上富集，这与使用其他模型的先前数据一致。我们首次表明，低氧诱导的整个基因组染色质可及性的变化主要依赖于 HIF，在再氧合后迅速可逆，并且部分地通过 HIF-α 稳定模拟，与分子双加氧酶抑制无关。这项工作表明，HIF 是缺氧条件下染色质可及性改变的核心，并且对我们理解缺氧和 HIF 对基因表达的调控具有重要意义。