title: Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism.
abstract: The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, ∼50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Saikumari Y
authors.initials: SY
authors.lastname: Krishnaiah
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Altman
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Growe
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Rhoades
authors.affiliation: Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Coldren
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Venkataraman
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Olarerin-George
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Francey
authors.affiliation: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Saiveda
authors.initials: S
authors.lastname: Girish
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Selby
authors.affiliation: Chemical and Biological Engineering and Molecular Biology and Genetics, Koc University, Rumeli Feneri Yolu, 34450 Sariyer, Istanbul, Turkey.
authors.forename: Sibel
authors.initials: S
authors.lastname: Cal
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ubeydullah
authors.initials: U
authors.lastname: Er
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Sianati
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: Department of Medicine and Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ron C
authors.initials: RC
authors.lastname: Anafi
authors.affiliation: Chemical and Biological Engineering and Molecular Biology and Genetics, Koc University, Rumeli Feneri Yolu, 34450 Sariyer, Istanbul, Turkey.
authors.forename: I Halil
authors.initials: IH
authors.lastname: Kavakli
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Aziz
authors.initials: A
authors.lastname: Sancar
authors.affiliation: Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: john.hogenesch@cchmc.org.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: aalim@mail.med.upenn.edu.
authors.forename: Aalim M
authors.initials: AM
authors.lastname: Weljie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D003401:Creatine / Q000378:metabolism; D056931:Cryptochromes / Q000378:metabolism; D053263:Gene Regulatory Networks; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D055442:Metabolome / Q000235:genetics*; D051379:Mice; D009584:Nitrogen / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D056931:Cryptochromes; D003401:Creatine; D009584:Nitrogen
keywords: LCMS; chronometabolism; chronopharmacology; circadian clock; circadian metabolism; mass spectrometry; metabolomics; translational transcription feedback loop