Cold-induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm.

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. Sub‐physiological temperatures mimicking surgery‐associated deep hypothermia reset the circadian clock in human cells by nuclear sequestration and warming‐induced re‐release of REV‐ERBα transcripts.

将患者冷却到亚生理温度是现代医学不可或缺的一部分。我们发现，寒冷暴露会诱导人类细胞的高阶染色质和基因表达谱发生温度特异性变化。这些变化在18°C时尤为显著，这个温度与手术中接受控制性深低温的患者所经历的温度相同。暴露于18°C的细胞在很大程度上表现出核内受限的转录组变化。这包括编码核心生物钟负向调节臂成分的信使核糖核酸（mRNA）在核内的积累，最显著的是REV - ERBα。这种反应伴随着高阶染色质的压缩以及信使核糖核蛋白（mRNP）与核孔结合受阻。复温会逆转染色质压缩，并将转录本释放到细胞质中，触发一个负向调节臂基因蛋白脉冲，从而重置生物钟。我们表明，寒冷诱导的REV - ERBα上调足以触发这种重置。我们的研究结果揭示了细胞对寒冷反应的原理，在涉及治疗性深低温的当前和未来应用中必须考虑这些原理。 模拟手术相关深低温的亚生理温度通过REV - ERBα转录本的核内隔离以及复温诱导的重新释放来重置人类细胞的生物钟。