Alternative splicing of clock transcript mediates the response of circadian clocks to temperature changes

May 20, 2024bioRxiv : the preprint server for biology

How changes in clock gene processing help circadian clocks respond to temperature shifts

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Abstract

Cold temperature induces the production of a specific CLK isoform that lacks four amino acids, including a phosphorylation site.

Circadian clocks adjust biological rhythms in response to temperature changes throughout the year.
Temperature-sensitive alternative splicing of certain genes regulates seasonal adaptations and clock function.
The CLK isoform produced at cold temperatures, termed CLK-cold, has a deletion that affects its DNA binding ability.
Phosphorylation at serine 13 reduces CLK's interaction with DNA, influencing its occupancy at clock gene promoters.
Higher levels of CLK-cold are associated with increased transcriptional output of clock genes in cold conditions.

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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, seasonal adaptations and temperature compensation are regulated by temperature-sensitive alternative splicing (AS) of() and() genes that encode key transcriptional repressors of clock gene expression. Although() 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 whetherexhibits AS in response to temperature and the functional changes of the differentially spliced transcripts. We observed thattranscripts indeed undergo temperature-sensitive AS. Specifically, cold temperature leads to the production of an alternativetranscript, hereinafter termed-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 CK1α-dependent phosphorylation site, is among the four amino acids deleted in CLK-cold protein. Using a combination of transgenic fly, tissue culture, andexperiments, 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. Drosophila period per timeless tim clock clk clk clk clk clk in vitro

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Alternative splicing of clock transcript mediates the response of circadian clocks to temperature changes

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