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Circadian gene variants and the skeletal muscle circadian clock contribute to the evolutionary divergence in longevity across Drosophila populations

ABSTRACT: Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although circadian rhythms have been implicated in multiple aspects of aging, it remains uncertain whether evolutionary selection of circadian cycle gene variants contributes to changes in longevity and aging traits within animal populations. We have sequenced the genomes of Drosophila melanogaster strains with exceptional longevity that were obtained via multiple rounds of selection for reduced senescence from a parental strain. Preservation of youthful muscle gene expression and function is seen during aging in these strains and is primarily due to intergenic polymorphisms rather than to mutations in coding sequences. Expression of transcriptional regulators of the circadian machinery is highly modulated, with higher period and timeless and lower cycle expression in strains with delayed aging compared to the parental strain. These changes in the expression of circadian core components associate with changes in the amplitude and specificity of the circadian transcriptome. Moreover, a muscle-specific increase in timeless expression to levels similar to long-lived lines extends lifespan. Altogether, these findings indicate that circadian clock gene variants contribute to shaping aging traits and to the evolutionarily divergence in longevity within a species.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE129922 | GEO | 2019/06/06

REPOSITORIES: GEO

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Project description:Circadian rhythms are daily oscillations in metabolism and physiology and are generated by the circadian clock. In fruit fly Drosophila, the circadian clock is generated by a transcription-translation feedback loop in which the positive arm components Clock and Cycle activate the expression of the Period and Timeless genes of negative arm, as well as other circadian clock-regulated genes. After being retained in the cytoplasm, the Period and Timeless proteins then migrate to the nucleus to inhibit the Clock/Cycle transactivity by protein-protein interactions (PPIs). The endogenous circadian clock is synchronized with the geological (solar) clock via photoreceptors. Drosophila Cryptochrome protein functions as a circadian photoreceptor. In the early morning, exposure of Cryptochrome to light causes a conformational change in it which results in the formation of new PPIs. Light-activated Cryptochrome interacts with the core clock protein Timeless and the E3 ubiquitin ligase-substrate adaptor protein Jetlag, which results in the ubiquitylation of Timeless by Jetlag-E3 ligase complex and then degradation of Timeless within minutes by proteasome system. Rapid degradation of Timeless and then its partner protein Period, because of its instability in the absence of Timeless, relieves the inhibition on the Clock/Cycle transcription factors suddenly. Therefore, Clock/Cycle-driven expression of circadian clock-regulated genes are induced again, which is the restart of the circadian oscillation or the resetting of the clock. Following Timeless degradation, Cryptochrome is also degraded so the photoreceptor mechanism does not start a new resetting signal until all the required factors are re-synthesized in a circadian manner. Light-dependent degradation of Drosophila Cryptochrome can be observed in Drosophila S2 cell line in culture. In this project, we aimed at finding the interactome of Cryptochrome protein in Drosophila S2 cell line under light and in the dark using proximity labeling method. Because of the fast kinetics of Cryptochrome degradation, we chose the enzymes that can saturate in less than one hour. TurboID (TID) and APEX2 enzymes label proteins with biotin in the proximity even though they work with different mechanisms. They were fused to Cryptochrome protein, and proximity labeling was performed in the dark or under light. We have identified novel light-dependent or -independent interactors of Drosophila Cryptochrome and confirmed some of them using classical coimmunoprecipitation technique.

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Circadian gene variants and the skeletal muscle circadian clock contribute to the evolutionary divergence in longevity across Drosophila populations

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