Circadian acetylome reveals regulation of mitochondrial metabolic pathways

The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock−/−) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock−/− mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state.

[1]  K. Valgepea,et al.  Comparison and applications of label-free absolute proteome quantification methods on Escherichia coli. , 2012, Journal of proteomics.

[2]  Pierre Baldi,et al.  CircadiOmics: integrating circadian genomics, transcriptomics, proteomics and metabolomics , 2012, Nature Methods.

[3]  Ramón Doallo,et al.  CircadiOmics: integrating circadian genomics, transcriptomics, proteomics and metabolomics , 2012, Nature Methods.

[4]  Pierre Baldi,et al.  Cyber-T web server: differential analysis of high-throughput data , 2012, Nucleic Acids Res..

[5]  K. Wellen,et al.  A two-way street: reciprocal regulation of metabolism and signalling , 2012, Nature Reviews Molecular Cell Biology.

[6]  Pierre Baldi,et al.  Coordination of the transcriptome and metabolome by the circadian clock , 2012, Proceedings of the National Academy of Sciences.

[7]  Steven A. Brown,et al.  The human circadian metabolome , 2012, Proceedings of the National Academy of Sciences.

[8]  P. Becker,et al.  Probing the Conformation of the ISWI ATPase Domain With Genetically Encoded Photoreactive Crosslinkers and Mass Spectrometry* , 2011, Molecular & Cellular Proteomics.

[9]  J. Eng,et al.  The fasted/fed mouse metabolic acetylome: N6-acetylation differences suggest acetylation coordinates organ-specific fuel switching. , 2011, Journal of proteome research.

[10]  Bing Li,et al.  Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. , 2011, Molecular cell.

[11]  M. Caron,et al.  Quantitative Label-Free Phosphoproteomics Strategy for Multifaceted Experimental Designs , 2011, Analytical chemistry.

[12]  M. Mann,et al.  More than 100,000 detectable peptide species elute in single shotgun proteomics runs but the majority is inaccessible to data-dependent LC-MS/MS. , 2011, Journal of proteome research.

[13]  Kun-Liang Guan,et al.  Regulation of intermediary metabolism by protein acetylation. , 2011, Trends in biochemical sciences.

[14]  Andrew J. Millar,et al.  Circadian rhythms persist without transcription in a eukaryote , 2010, Nature.

[15]  P. Sassone-Corsi,et al.  Mammalian circadian clock and metabolism – the epigenetic link , 2010, Journal of Cell Science.

[16]  Karl Kornacker,et al.  JTK_CYCLE: An Efficient Nonparametric Algorithm for Detecting Rhythmic Components in Genome-Scale Data Sets , 2010, Journal of biological rhythms.

[17]  Y. Xiong,et al.  Generation of acetyllysine antibodies and affinity enrichment of acetylated peptides , 2010, Nature Protocols.

[18]  Yixue Li,et al.  Regulation of Cellular Metabolism by Protein Lysine Acetylation , 2010, Science.

[19]  Robert V Farese,et al.  SIRT 3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation , 2010 .

[20]  Paolo Sassone-Corsi,et al.  Metabolism and cancer: the circadian clock connection , 2009, Nature Reviews Cancer.

[21]  S. Panda,et al.  AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation , 2009, Science.

[22]  Damian Fermin,et al.  Calorie restriction alters mitochondrial protein acetylation , 2009, Aging cell.

[23]  M. Mann,et al.  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions , 2009, Science.

[24]  P. Sassone-Corsi,et al.  Circadian Control of the NAD+ Salvage Pathway by CLOCK-SIRT1 , 2009, Science.

[25]  J. Takahashi,et al.  Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis , 2009, Science.

[26]  T. Kino,et al.  Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  Satchidananda Panda,et al.  Harmonics of Circadian Gene Transcription in Mammals , 2009, PLoS genetics.

[28]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[29]  D. Wallace.  Mitochondria, bioenergetics, and the epigenome in eukaryotic and human evolution. , 2009, Cold Spring Harbor symposia on quantitative biology.

[30]  Jürgen Cox,et al.  A practical guide to the MaxQuant computational platform for SILAC-based quantitative proteomics , 2009, Nature Protocols.

[31]  Joseph S. Takahashi,et al.  The Meter of Metabolism , 2008, Cell.

[32]  Florian Kreppel,et al.  SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation , 2008, Cell.

[33]  Paolo Sassone-Corsi,et al.  The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control , 2008, Cell.

[34]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[35]  Paolo Sassone-Corsi,et al.  CLOCK-mediated acetylation of BMAL1 controls circadian function , 2007, Nature.

[36]  Joseph S. Takahashi,et al.  Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression , 2007, Cell.

[37]  Michele Pagano,et al.  SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins , 2007, Science.

[38]  M. Pagano,et al.  The After-Hours Mutant Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period , 2007, Science.

[39]  Sehyung Cho,et al.  Rapid activation of CLOCK by Ca2+‐dependent protein kinase C mediates resetting of the mammalian circadian clock , 2007, EMBO reports.

[40]  Erin L. McDearmon,et al.  Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation , 2007, Proceedings of the National Academy of Sciences.

[41]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[42]  D. Virshup,et al.  Post-translational modifications regulate the ticking of the circadian clock , 2007, Nature Reviews Molecular Cell Biology.

[43]  J. Hogenesch,et al.  High-resolution time course analysis of gene expression from pituitary. , 2007, Cold Spring Harbor symposia on quantitative biology.

[44]  N. Grishin,et al.  Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. , 2006, Molecular cell.

[45]  M. Yanagisawa,et al.  The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker , 2006, Proceedings of the National Academy of Sciences.

[46]  Eric Verdin,et al.  Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2 , 2006, Proceedings of the National Academy of Sciences.

[47]  Kathryn S. Lilley,et al.  Circadian Orchestration of the Hepatic Proteome , 2006, Current Biology.

[48]  Jason P. DeBruyne,et al.  A Clock Shock: Mouse CLOCK Is Not Required for Circadian Oscillator Function , 2006, Neuron.

[49]  M. Mann,et al.  Parts per Million Mass Accuracy on an Orbitrap Mass Spectrometer via Lock Mass Injection into a C-trap*S , 2005, Molecular & Cellular Proteomics.

[50]  Paolo Sassone-Corsi,et al.  Circadian Clock Control by SUMOylation of BMAL1 , 2005, Science.

[51]  Y. E. Chin,et al.  Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue , 2005, Science.

[52]  Paolo Sassone-Corsi,et al.  A Web of Circadian Pacemakers , 2002, Cell.

[53]  J. C. Evans,et al.  Betaine-homocysteine methyltransferase: zinc in a distorted barrel. , 2002, Structure.

[54]  Ulf Hellman,et al.  Control of Smad7 stability by competition between acetylation and ubiquitination. , 2002, Molecular cell.

[55]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[56]  R. Akhtar,et al.  Circadian Cycling of the Mouse Liver Transcriptome, as Revealed by cDNA Microarray, Is Driven by the Suprachiasmatic Nucleus , 2002, Current Biology.

[57]  Jennifer J. Loros,et al.  Circadian Programs of Transcriptional Activation, Signaling, and Protein Turnover Revealed by Microarray Analysis of Mammalian Cells , 2002, Current Biology.

[58]  E. Nishida,et al.  Control of Intracellular Dynamics of Mammalian Period Proteins by Casein Kinase I ε (CKIε) and CKIδ in Cultured Cells , 2002, Molecular and Cellular Biology.

[59]  Toshiyuki Okano,et al.  Mitogen-activated Protein Kinase Phosphorylates and Negatively Regulates Basic Helix-Loop-Helix-PAS Transcription Factor BMAL1* , 2002, The Journal of Biological Chemistry.

[60]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[61]  Pierre Baldi,et al.  A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes , 2001, Bioinform..

[62]  Lei Zeng,et al.  Structure and ligand of a histone acetyltransferase bromodomain , 1999, Nature.

[63]  V. Ogryzko,et al.  Regulation of activity of the transcription factor GATA-1 by acetylation , 1998, Nature.

[64]  M. Grunstein.  Histone acetylation in chromatin structure and transcription , 1997, Nature.

[65]  Wei Gu,et al.  Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain , 1997, Cell.

[66]  N. Hirokawa,et al.  Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau. , 1992, Journal of cell science.

[67]  N. Shimizu,et al.  The human ATP synthase beta subunit gene: sequence analysis, chromosome assignment, and differential expression. , 1989, Genomics.

[68]  J. Rosenbaum,et al.  Chlamydomonas alpha-tubulin is posttranslationally modified by acetylation on the epsilon-amino group of a lysine. , 1985, Biochemistry.

[69]  A. Meister,et al.  Bicarbonate-dependent cleavage of adenosine triphosphate and other reactions catalyzed by Escherichia coli carbamyl phosphate synthetase. , 1966, Biochemistry.