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. Synopsis How human cells respond to cold temperatures such as surgery‐associated deep hypothermia is largely elusive. Here, low temperatures are found to affect chromatin architecture, shape temperature‐specific nuclear and cytoplasmic transcriptomes, and subsequently reset the circadian rhythm in human cells. Exposure of human cells to varying sub‐physiological temperatures induces chromatin compaction in a non‐linear fashion. Chromatin compaction at 18°C correlates with nuclear retention of mRNAs. Incubation at 18°C forces the nuclear‐restricted upregulation of mRNAs encoding circadian clock repressor/co-repressor genes, most notably REV‐ERBα. Rewarming cells to 37°C causes release of nuclear‐accumulated mRNAs into the cytoplasm, resetting the cellular circadian rhythm. Graphical Abstract 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.