title: Integrative analysis of circadian transcriptome and metabolic network reveals the role of de novo purine synthesis in circadian control of cell cycle.
abstract: Metabolism is the major output of the circadian clock in many organisms. We developed a computational method to integrate both circadian gene expression and metabolic network. Applying this method to zebrafish circadian transcriptome, we have identified large clusters of metabolic genes containing mostly genes in purine and pyrimidine metabolism in the metabolic network showing similar circadian phases. Our metabolomics analysis found that the level of inosine 5'-monophosphate (IMP), an intermediate metabolite in de novo purine synthesis, showed significant circadian oscillation in larval zebrafish. We focused on IMP dehydrogenase (impdh), a rate-limiting enzyme in de novo purine synthesis, with three circadian oscillating gene homologs: impdh1a, impdh1b and impdh2. Functional analysis revealed that impdh2 contributes to the daily rhythm of S phase in the cell cycle while impdh1a contributes to ocular development and pigment synthesis. The three zebrafish homologs of impdh are likely regulated by different circadian transcription factors. We propose that the circadian regulation of de novo purine synthesis that supplies crucial building blocks for DNA replication is an important mechanism conferring circadian rhythmicity on the cell cycle. Our method is widely applicable to study the impact of circadian transcriptome on metabolism in complex organisms.
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany; Institute for Biological Interfaces, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Karlsruhe, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Görling
authors.affiliation: Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany; Institute for Biological Interfaces, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Karlsruhe, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Luy
authors.affiliation: Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiulin
authors.initials: J
authors.lastname: Du
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D016000:Cluster Analysis; D029941:Fish Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007168:IMP Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D011687:Purines / Q000378:metabolism*; D059467:Transcriptome / Q000502:physiology*; D015027:Zebrafish
chemical_list: D029941:Fish Proteins; D011687:Purines; D007168:IMP Dehydrogenase