Organisms on the earth produced a rhythm with a 24-hour cycle to adapt to day/night variations in the environment, which is known as circadian rhythm. This rhythm is present in various biological activities, such as the sleep/wake cycle of human and many other animals, the photosynthesis of plants, the sporulation of fungi, and the cell division of bacteria. Circadian rhythm is driven by the endogenous circadian clock. Disturbances of circadian clock and circadian rhythm not only affects sleep, but also increases the risk of various diseases such as metabolic diseases, cancer, and mental diseases.
In 2017, American scientists Jeffrey C. Hall, Michael Rosbash and Michael W. Young received the Nobel Prize in Physiology or Medicine for their contributions to revealing the circadian clock of fruit flies at the molecular level. The molecular regulatory mechanism of the circadian clock is highly conserved among different species. From prokaryotes such as cyanobacteria to humans, the phosphorylation of clock proteins regulated by protein kinases is the key to determine the pace of the clock. Phosphorylation regulates the subcellular localization, the stability and the activity of clock proteins, which all exhibit rhythmic changes with a 24-hour period. This serves as the molecular basis of the circadian rhythms in various behaviors and physiological processes. In recent years, studies in the liver of mice have unveiled that rhythmic phosphorylation is not only present in the several proteins that form the circadian clock, but is widespread throughout the proteome. About 1/4 of the phosphorylation sites that can be detected display circadian rhythm! But what is the physiological significance of these rhythmic phosphorylation and how are they regulated? These questions have not been answered yet.
Recently, the teams of Professors Zhang Luoying and Xue Yu of the College of Life Science and Technology at Huazhong University of Science and Technology published a research paper in Nature Communications titled: Integrated omics in Drosophila uncover a circadian kinome. This study uses systematic biology to study the rhythm of protein phosphorylation and explore its function and regulatory mechanism.
The authors conducted time series profiling of transcriptomes, proteomes and phosphoproteomes from fly heads. They developed a pipeline iCMod (integrating circadian multi-omics data) to integrate the multi-omics data and analyze the results. 17% of the phosphorylation sites (789) in the fly head showed a circadian rhythm. The vast majority of these sites lost rhythms when a core clock gene is mutated, suggesting that the rhythmic phosphorylation of these sites is driven by the molecular clock. 27 kinases were predicted to be involved in phosphorylating these sites, including 7 kinases already known to be important regulators of the fly clock. The authors then tested the remaining 20 kinases and identified 3 new kinases that regulate fly locomotor rhythm. Based on the known and predicted kinase substrate relationships, they built a signal network for these 10 (including 7 known and 3 new) kinases. This network can explain how these kinases act together to regulate the molecular clock and locomotor rhythm. According to the predicted results, the master regulator of the network is a newly identified circadian kinase GASKET (GSKT). Further molecular analysis revealed that GSKT may regulates the molecular clock and locomotor rhythm by down-regulating the level of clock protein TIMELESS.
Two PhD students of the College of Life Science and Technology at Huazhong University of Science and Technology, Wang Chenwei and Shui Ke, are the co-first authors of the paper. Professors Xue Yu and Zhang Luoying are co-corresponding authors. This research is supported by Natural Science Foundation of China, the Special Project on Precision Medicine under the National Key R&D Program, and the National Program for Support of Top-Notch Young Professionals.