缺氧和 HIF 对染色质可及性的调控。

Regulation of chromatin accessibility by hypoxia and HIF.

机构信息

Department of Molecular Physiology and Cell Signalling, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown Street, Liverpool L697ZB, U.K.

出版信息

Biochem J. 2022 Mar 31;479(6):767-786. doi: 10.1042/BCJ20220008.

Abstract

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.

摘要

氧气供应减少(缺氧)可以作为生理过程(如发育)中的信号提示,也可以在病理条件下(如癌症或缺血性疾病)发挥作用。因此,了解细胞和生物体如何对缺氧做出反应非常重要。一类称为缺氧诱导因子 (HIF) 的转录因子家族协调了对缺氧生存和适应所需的转录程序。然而,HIF 对染色质可及性的影响目前尚不清楚。在这里,我们使用 ATAC-seq 对染色质可及性进行全基因组作图,发现缺氧诱导的染色质可及性的局部变化在一组缺氧转录响应基因中富集,与之前使用其他模型得到的数据一致。我们首次表明,基因组范围内的缺氧诱导的染色质可及性变化主要依赖于 HIF,在重新供氧时可迅速逆转,并且部分由 HIF-α稳定化模拟,而不依赖于分子双氧酶抑制。这项工作表明 HIF 是缺氧导致染色质可及性改变的核心,这对我们理解缺氧和 HIF 对基因表达调控具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cb7/9022986/14dfcef44b92/BCJ-479-767-g0001.jpg

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