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

Fischl, Harry; McManus, David; Oldenkamp, Roel; Schermelleh, Lothar; Mellor, Jane; Jagannath, Aarti; Furger, André

doi:10.15252/embj.2020105604

Cited by 14 publications

(4 citation statements)

References 87 publications

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“…Future studies are required to fully understand the role of temperature-sensitive AS on the entrainment of peripheral clocks by body temperature rhythms. It is also interesting to point out that cold temperature also induces mRNA expression of several CLOCK target genes in human cardiomyocytes 76 . Similarly, lowered body temperature during hibernation of brown bears also results in elevated mRNA level of a CLOCK target gene, cry2 77 .…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing ofclocktranscript mediates the response of circadian clocks to temperature changes

Cai,

Chow,

Hidalgo

et al. 2024

Preprint

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Circadian clocks respond to temperature changes over the calendar year, allowing organisms to adjust their daily biological rhythms to optimize health and fitness. In Drosophila, seasonal adaptations and temperature compensation are regulated by temperature-sensitive alternative splicing (AS) of period (per) and timeless (tim) genes that encode key transcriptional repressors of clock gene expression. Although clock (clk) gene encodes the critical activator of clock gene expression, AS of its transcripts and its potential role in temperature regulation of clock function have not been explored. We therefore sought to investigate whether clk exhibits AS in response to temperature and the functional changes of the differentially spliced transcripts. We observed that clk transcripts indeed undergo temperature-sensitive AS. Specifically, cold temperature leads to the production of an alternative clk transcript, hereinafter termed clk-cold, which encodes a CLK isoform with an in-frame deletion of four amino acids proximal to the DNA binding domain. Notably, serine 13 (S13), which we found to be a CK1alpha-dependent phosphorylation site, is among the four amino acids deleted in CLK-cold protein. Using a combination of transgenic fly, tissue culture, and in vitro experiments, we demonstrated that upon phosphorylation at CLK(S13), CLK-DNA interaction is reduced, thus decreasing CLK occupancy at clock gene promoters. This is in agreement with our findings that CLK occupancy at clock genes and transcriptional output are elevated at cold temperature, which can be explained by the higher amounts of CLK-cold isoforms that lack S13 residue. This study provides new insights into the complex collaboration between AS and phospho-regulation in shaping temperature responses of the circadian clock.

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Section: Discussionmentioning

confidence: 99%

Alternative splicing ofclocktranscript mediates the response of circadian clocks to temperature changes

Cai,

Chow,

Hidalgo

et al. 2024

Preprint

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“…One important factor contributing to the PRT could be the rapid temperature changes during the HIB-DT and HIB-PA cycles. In cultured human cell lines or mouse SCN slices, rewarming from the cold to euthermic conditions resets the phase of circadian clock gene expression [ 57 , 58 ]. Similarly, a phase reset of the clock gene expression rhythm may occur during rewarming from the hypothermic conditions during hibernation.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous recurrence of a summer-like diel rhythm in the body temperature of the Syrian hamster after hibernation

Nakagawa,

Yamaguchi

2023

Proc. R. Soc. B.

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Mammalian hibernation is a survival strategy characterized by metabolic suppression and drastically lowering body temperature (Tb), used during harsh seasons with food shortages and cold. The Syrian hamster commences hibernation in response to a short photoperiod and cold but spontaneously concludes hibernation after several months without environmental cues. Little is known about the changes in diel rhythms during hibernation. Using long-term and high-resolution Tb data, we analysed the diel Tb rhythm time-course changes in Syrian hamsters raised under summer-like conditions (long photoperiod (LP) and warm; LP-warm) and transferred to winter-like conditions (short photoperiod (SP) and cold; SP-cold). The diel Tb rhythm was undetectable during the hibernation period (HIBP), reappearing after the HIBP. The phase of this returning rhythm reverted to the LP entrainment phase characteristics despite the ambient SP and then re-entrained to the ambient SP as if the hamsters were transferred from the LP-warm to SP-cold conditions. The diel Tb rhythm reverted from the SP- to LP-type in a hibernation-dependent manner. Under constant dark and cold conditions, the circadian Tb rhythm recovered without photic stimuli following the HIBP. These findings suggest that hibernation involves a program that anticipates the ambient photoperiod when animals emerge from hibernation.

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“…While our method constitutes a reliable, non-invasive and well tunable way to induce chromatin motion in cell nuclei and study its relaxation behaviors, our perturbations bear further potential to gain insight into the physical chemistry that underlies temperature dependent chromatin organization. Temperature dependent changes in chromatin compaction have been reported after bulk cooling of live cell nuclei (Fischl et al, 2020), albeit on the time scale of hours. On shorter time scales, reversible changes in nuclear volume have been observed after homogenous temperature increases (ΔT=18°C) in isolated nuclei (Chan et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Non-invasive Chromatin Deformation and Measurement of Differential Mechanical Properties in the Nucleus

Seelbinder

Jain

Erben

et al. 2021

Preprint

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The nucleus is highly organized to facilitate coordinated gene transcription. Measuring the rheological properties of the nucleus and its sub-compartments will be crucial to understand the principles underlying nuclear organization. Here, we show that strongly localized temperature gradients (approaching 1°C /μm) can lead to substantial intra-nuclear chromatin displacements (>1 μm), while nuclear area and lamina shape remain unaffected. Using particle image velocimetry (PIV), intra-nuclear displacement fields can be calculated and converted into spatio-temporally resolved maps of various strain components. Using this approach, we show that chromatin displacements are highly reversible, indicating that elastic contributions are dominant in maintaining nuclear organization on the time scale of seconds. In genetically inverted nuclei, centrally compacted heterochromatin displays high resistance to deformation, giving a rigid, solid-like appearance. Correlating spatially resolved strain maps with fluorescent reporters in conventional interphase nuclei reveals that various nuclear compartments possess distinct mechanical identities. Surprisingly, both densely and loosely packed chromatin showed high resistance to deformation, compared to medium dense chromatin. Equally, nucleoli display particularly high rigidity and strong local anchoring to heterochromatin. Our results establish how localized temperature gradients can be used to drive nuclear compartments out of mechanical equilibrium to obtain spatial maps of their material responses.Main FindingsNovel non-invasive active micro-rheology method to probe spatial intranuclear material responses, unhindered by the nuclear lamina, using strongly localized temperature gradientsChromatin shows both elastic and viscous properties at the mesoscale with a retardation time of τ ∼ 1sCompacted heterochromatin in a model of nuclear inversion shows high resistance to deformation, suggesting dominantly solid-like behaviorThe nucleus displays spatially distinct material properties for different compartmentsThe nucleolus shows high resistance to deformation on the time scale of secondsImmobile nucleoli appear solidly anchored to and retain the deformation of surrounding chromatin

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

Cited by 14 publications

References 87 publications

Alternative splicing ofclocktranscript mediates the response of circadian clocks to temperature changes

Alternative splicing ofclocktranscript mediates the response of circadian clocks to temperature changes

Spontaneous recurrence of a summer-like diel rhythm in the body temperature of the Syrian hamster after hibernation

Non-invasive Chromatin Deformation and Measurement of Differential Mechanical Properties in the Nucleus

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