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表观遗传改变促进缺氧状态下的转录和翻译程序。

Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.

作者信息

Watt Kathleen, Dauber Bianca, Szkop Krzysztof J, Lee Laura, Jovanovic Predrag, Chen Shan, Palia Ranveer, Vassalakis Julia A, Cooper Tyler T, Papadopoli David, Masvidal Laìa, Jewer Michael, Tandoc Kristofferson, Plummer Hannah, Lajoie Gilles A, Topisirovic Ivan, Larsson Ola, Postovit Lynne-Marie

机构信息

Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.

出版信息

Nat Cell Biol. 2025 Nov;27(11):1965-1981. doi: 10.1038/s41556-025-01786-8. Epub 2025 Oct 16.

DOI:10.1038/s41556-025-01786-8
PMID:41102449
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12611764/
Abstract

Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5'UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5'UTRome.

摘要

细胞对应激的适应需要转录和转录后基因表达程序之间进行不完全清楚的协调。在这里，通过对T47D乳腺癌细胞和H9人胚胎干细胞中的缺氧依赖性转录组、表观基因组和翻译组进行定量分析，我们发现转录起始位点（TSS）选择存在普遍变化，这与核小体重新定位以及H3K4me3分布改变有关。值得注意的是，在不存在缺氧的情况下，通过对H3K4me3进行药理学调节可诱导或逆转缺氧相关的TSS转换，这确定了H3K4me3在TSS选择中的作用，且该作用独立于HIF1转录程序。通过重塑5'非翻译区（5'UTR），TSS转换选择性地改变蛋白质合成，包括增强编码丙酮酸脱氢酶激酶1的信使核糖核酸（mRNA）的翻译，这对于代谢适应缺氧至关重要。这些结果证明了在缺氧期间由5'UTR表观遗传重编程驱动的一种以前未被认识的翻译调控机制。

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