Epigenetic coordination of transcriptional and translational programs in hypoxia. [ChIP-Seq]

Stress adaptation entails perturbations in transcriptional and post-transcriptional mechanisms of regulation of gene expression, but how these programs are coordinated remains largely unknown. To address this, we systematically interrogated the effects of hypoxia on transcriptomes, epigenomes and translatomes of T47D breast cancer cells and H9 human embryonic stem cells. This revealed that hypoxia-induced alterations in H3K4me3 exert unexpectedly minimal effects on transcript abundances. Instead, they were associated with pervasive changes in the transcription start site (TSS) selection, subsequent 5’UTR remodeling, and reshaping of translational landscapes. Importantly, this epigenetically-driven reprograming of translation is distinct from HIF1-dependent transcriptional mechanisms or integrated stress response- or mTOR-guided translational reprogramming. Indeed, comparable effects on TSS selection and 5'UTR remodeling were observed when H3K4me3 was pharmacologically stimulated in the absence of induction of HIF, ISR or modulation of mTOR signaling. These results demonstrate a previously unappreciated physiologically relevant mechanism of translational regulation driven by epigenetic reprograming of the 5’UTRome which is orchestrated with other hypoxia-triggered adaptive mechanisms. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for the histone modification H3K4me3 in hypoxia and normoxia-treated T47D breast cancer and H9 human embryonic stem cells.

应激适应会引发基因表达调控的转录及转录后机制发生扰动，但这些调控程序如何协同运作，目前仍知之甚少。为解答这一科学问题，我们系统探究了低氧对T47D乳腺癌细胞与H9人胚胎干细胞的转录组、表观组及翻译组的影响。研究发现，低氧诱导的组蛋白H3赖氨酸4三甲基化（H3K4me3）改变对转录本丰度的影响出乎意料地微弱。与之相反，这些改变与转录起始位点（TSS）的广泛变化、后续的5'非翻译区（5'UTR）重塑以及翻译调控图谱的重塑密切相关。值得注意的是，这种由表观遗传驱动的翻译重编程，与缺氧诱导因子1（HIF1）依赖的转录机制、整合应激反应（ISR）或雷帕霉素靶蛋白（mTOR）介导的翻译重编程均存在显著差异。事实上，在不诱导HIF、不激活整合应激反应或不调控mTOR信号通路的情况下，通过药物手段激活H3K4me3时，同样观察到了对TSS选择与5'UTR重塑的类似影响。上述结果揭示了一种此前未被关注的、具有生理相关性的翻译调控机制：该机制由5'UTR组的表观遗传重编程驱动，并与低氧触发的其他适应机制协同运作。本数据集包含对低氧与常氧处理的T47D乳腺癌细胞及H9人胚胎干细胞中组蛋白H3赖氨酸4三甲基化（H3K4me3）开展染色质免疫沉淀测序（ChIP-seq）的相关实验数据。