Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm
Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm
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寒冷诱导的染色质压缩和时钟 mRNA 的核保留重置了昼夜节律
DOI：
10.1101/2020.06.05.127290
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Fischl H
中科院分区：
文献类型：
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作者：
Fischl H
将患者冷却至亚生理温度是现代医学不可或缺的一部分。我们表明，冷暴露诱导温度特异性变化的高阶染色质和人类细胞的基因表达谱。这些变化在18 ° C时特别显著，该温度与手术期间接受受控深低温的患者所经历的温度同义。暴露于18 ° C的细胞表现出很大程度上的核限制性转录组变化。这些包括核心昼夜节律钟负肢编码成分的mRNA的核积累，最明显的是REV-ERB α。这种反应伴随着高级染色质的压实和mRNP接合核孔的阻碍。复温逆转了染色质的致密化，并将转录物释放到细胞质中，触发了负肢基因蛋白的脉冲，重置了生物钟。我们发现，冷诱导的REV-ERB α上调足以触发这种重置。我们的研究结果揭示了细胞冷反应的原则，必须考虑目前和未来的应用，涉及治疗深低温。
Cooling patients to sub‐physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature‐specific changes to the higher‐order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18°C, a temperature synonymous with that experienced by patients undergoing controlled deep hypothermia during surgery. Cells exposed to 18°C exhibit largely nuclear‐restricted transcriptome changes. These include the nuclear accumulation of mRNAs encoding components of the negative limbs of the core circadian clock, most notably REV‐ERBα. This response is accompanied by compaction of higher‐order chromatin and hindrance of mRNPs from engaging nuclear pores. Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of negative limb gene proteins that reset the circadian clock. We show that cold‐induced upregulation of REV‐ERBα is sufficient to trigger this reset. Our findings uncover principles of the cellular cold response that must be considered for current and future applications involving therapeutic deep hypothermia.