Systematic Study Of The Regulatory Mechanism And Function Of Circadian Rhythm

Circadian rhythm,as a biological phenomenon widely existing in nature,has a long history of evolution,and is a reflection of the ability of life to adapt to the outside world.The daily light-dark changes affect a series of biological activities,such as the proliferation of microorganisms,energy synthesis of plants,and animal behavior.In order to adapt to the light-dark changes,the organisms evolved a special biological function which is called circadian clock.This clock not only regulates various behaviors and physiological activities,but also helps maintain homeostasis of various tissues and organs,but its specific regulatory mechanism and function are still largely unclear.Some studies have shown that rhythms exist at all levels of gene expression.To uncover the functions of circadian clock and circadian rhythm,we constructed a circadian gene database(circadian gene database,CGDB)covering multiple species and multiple parameters was constructed by collecting rhythmic gene data reported by published literatures and high-throughput data.Analysis of the CGDB database revealed that rhythmic genes are enriched in metabolic pathways in different species,suggesting that regulating metabolic rhythms is an evolutionarily conserved function of circadian clocks and circadian rhythms.Recent studies have shown that phosphorylation rhythms are widely present on many proteins,which may be a crucial mechanism that drives molecular rhythm,but the regulatory mechanism is still unclear.In this study,we integrated a set of omics data obtained in Drosophila heads at the transcriptome,proteome,and phosphoproteome levels,and developed a new rhythm algorithm i CMod(integrating circadian multi-omics data)to analyze multi-omics data.We identified 789 rhythmic oscillatory phosphorylation sites from a total of 4,686 phosphorylation sites.Using CGDB to assist our analysis,we predicted 27 circadian kinases to be important in phosphorylating these sites,including 7 already known to regulate circadian rhythm.We conducted genetic screens on the remaining kinases for effects on fly locomotor rhythm and found seven new kinases that can significantly affect the rhythm,which are gasket,Downstream of raf 1,casein kinase I ?,basket,gilgamesh,hemitterous and Asator.By analyzing the interactions between these 14 kinases,we reveal a network that This network can directly or indirectly regulate the rhythmic oscillations at m RNA,proteins and phosphorylation levels.We further found GASKET as a key regulator in this network,and it regulates stability of the core clock protein TIMELESS.In summary,this study reveals a circadian kinome that affects molecular oscillations at multi levels and behavioral rhythm.