Transcriptional architecture of the mammalian circadian clock

Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription–translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.

[1]  Thomas Cremer,et al.  The 4D nucleome: Evidence for a dynamic nuclear landscape based on co‐aligned active and inactive nuclear compartments , 2015, FEBS letters.

[2]  Paolo Sassone-Corsi,et al.  Time for Food: The Intimate Interplay between Nutrition, Metabolism, and the Circadian Clock , 2015, Cell.

[3]  Paolo Sassone-Corsi,et al.  Circadian clock proteins and immunity. , 2014, Immunity.

[4]  John T. Lis,et al.  Getting up to speed with transcription elongation by RNA polymerase II , 2015, Nature Reviews Molecular Cell Biology.

[5]  M. Mann,et al.  Histone monoubiquitination by Clock–Bmal1 complex marks Per1 and Per2 genes for circadian feedback , 2015, Nature Structural &Molecular Biology.

[6]  Danny Reinberg,et al.  Elongation by RNA polymerase II: the short and long of it. , 2004, Genes & development.

[7]  J. Takahashi,et al.  Cycling Transcriptional Networks Optimize Energy Utilization on a Genome Scale. , 2015, Cell reports.

[8]  Christian Gieger,et al.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk , 2010, Nature Genetics.

[9]  Xinran Liu,et al.  Competing E3 Ubiquitin Ligases Govern Circadian Periodicity by Degradation of CRY in Nucleus and Cytoplasm , 2013, Cell.

[10]  J. Takahashi,et al.  Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice , 2013, eLife.

[11]  R. Allada,et al.  Emerging roles for post-transcriptional regulation in circadian clocks , 2013, Nature Neuroscience.

[12]  P. Hardin,et al.  Molecular genetic analysis of circadian timekeeping in Drosophila. , 2011, Advances in genetics.

[13]  D. Weaver,et al.  The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1 , 2011, Proceedings of the National Academy of Sciences.

[14]  C. Chung,et al.  Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex , 2008, Molecular and Cellular Biology.

[15]  Minoru Tanaka,et al.  Positional Cloning of the Mouse Circadian Clock Gene , 1997, Cell.

[16]  Nacho Molina,et al.  Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK interaction with E boxes and requires the proteasome. , 2012, Molecular cell.

[17]  J. Dunlap Molecular Bases for Circadian Clocks , 1999, Cell.

[18]  V. Corces,et al.  Enhancer function: new insights into the regulation of tissue-specific gene expression , 2011, Nature Reviews Genetics.

[19]  John T. Lis,et al.  Defining mechanisms that regulate RNA polymerase II transcription in vivo , 2009, Nature.

[20]  R. Greenspan,et al.  Giving Time Purpose: The Synechococcus elongatus Clock in a Broader Network Context. , 2015, Annual Review of Genetics.

[21]  S. Yamaguchi,et al.  Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. , 2001, Genes & development.

[22]  Silja Martikainen,et al.  Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. , 2016, Cell metabolism.

[23]  Shannon N Nangle,et al.  Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex , 2014, eLife.

[24]  L. Feuk,et al.  Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain , 2011, Nature Structural &Molecular Biology.

[25]  Pierre Baldi,et al.  Cycles in spatial and temporal chromosomal organization driven by the circadian clock , 2013, Nature Structural &Molecular Biology.

[26]  J. Tyson,et al.  Design principles of biochemical oscillators , 2008, Nature Reviews Molecular Cell Biology.

[27]  Ueli Schibler,et al.  Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions , 2006, Nature Genetics.

[28]  John B. Hogenesch,et al.  Machine Learning Helps Identify CHRONO as a Circadian Clock Component , 2014, PLoS biology.

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

[30]  C. Johnson,et al.  Metabolic compensation and circadian resilience in prokaryotic cyanobacteria. , 2014, Annual review of biochemistry.

[31]  U. Alon Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[32]  J. Dunlap,et al.  Dissecting the mechanisms of the clock in Neurospora. , 2015, Methods in enzymology.

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

[34]  Christopher B. Burge,et al.  c-Myc Regulates Transcriptional Pause Release , 2010, Cell.

[35]  Paolo Sassone-Corsi,et al.  Circadian Regulator CLOCK Is a Histone Acetyltransferase , 2006, Cell.

[36]  Rachel S. Edgar,et al.  Histone methyltransferase MLL3 contributes to genome-scale circadian transcription , 2013, Proceedings of the National Academy of Sciences.

[37]  U. Albrecht,et al.  Timing to Perfection: The Biology of Central and Peripheral Circadian Clocks , 2012, Neuron.

[38]  E. Fredlund,et al.  PARP1- and CTCF-Mediated Interactions between Active and Repressed Chromatin at the Lamina Promote Oscillating Transcription. , 2015, Molecular cell.

[39]  Leah Barrera,et al.  A high-resolution map of active promoters in the human genome , 2005, Nature.

[40]  Paolo Sassone-Corsi,et al.  The histone methyltransferase MLL1 permits the oscillation of circadian gene expression , 2010, Nature Structural &Molecular Biology.

[41]  R. Shiekhattar,et al.  Architectural and Functional Commonalities between Enhancers and Promoters , 2015, Cell.

[42]  S. Munir Alam,et al.  C-terminal Repeat Domain Kinase I Phosphorylates Ser2 and Ser5 of RNA Polymerase II C-terminal Domain Repeats* , 2004, Journal of Biological Chemistry.

[43]  A. Sehgal,et al.  Ribosome profiling reveals an important role for translational control in circadian gene expression , 2015, Genome research.

[44]  C S Pittendrigh,et al.  Temporal organization: reflections of a Darwinian clock-watcher. , 1993, Annual review of physiology.

[45]  A. Kramer,et al.  Structures of Drosophila Cryptochrome and Mouse Cryptochrome1 Provide Insight into Circadian Function , 2013, Cell.

[46]  R. Young,et al.  Histone H3K27ac separates active from poised enhancers and predicts developmental state , 2010, Proceedings of the National Academy of Sciences.

[47]  Lucas C. Reineke,et al.  SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. , 2014, Cell reports.

[48]  Steven M. Reppert,et al.  Posttranslational Mechanisms Regulate the Mammalian Circadian Clock , 2001, Cell.

[49]  N. Rashid,et al.  Mammalian Period represses and de-represses transcription by displacing CLOCK–BMAL1 from promoters in a Cryptochrome-dependent manner , 2016, Proceedings of the National Academy of Sciences.

[50]  Jihwan Myung,et al.  A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock , 2014, PLoS biology.

[51]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[52]  C. Weitz,et al.  Temporal orchestration of repressive chromatin modifiers by circadian clock Period complexes , 2014, Nature Structural &Molecular Biology.

[53]  M. Rosbash,et al.  Nascent-Seq reveals novel features of mouse circadian transcriptional regulation , 2012, eLife.

[54]  J. Lieb,et al.  Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression* , 2014, The Journal of Biological Chemistry.

[55]  Colleen J Doherty,et al.  Circadian control of global gene expression patterns. , 2010, Annual review of genetics.

[56]  Jason P. DeBruyne,et al.  The Polycomb Group Protein EZH2 Is Required for Mammalian Circadian Clock Function*♦ , 2006, Journal of Biological Chemistry.

[57]  C. Partch,et al.  Emerging Models for the Molecular Basis of Mammalian Circadian Timing , 2014, Biochemistry.

[58]  Min Zhou,et al.  A Period2 Phosphoswitch Regulates and Temperature Compensates Circadian Period. , 2015, Molecular cell.

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

[60]  C. Weitz,et al.  A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery , 2013, Proceedings of the National Academy of Sciences.

[61]  C. Robertson McClung,et al.  Integrating circadian dynamics with physiological processes in plants , 2015, Nature Reviews Genetics.

[62]  Robert Tjian,et al.  Looping Back to Leap Forward: Transcription Enters a New Era , 2014, Cell.

[63]  J. Takahashi,et al.  Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. , 2000, Science.

[64]  J. Harper,et al.  SCFβ-TRCP Controls Clock-dependent Transcription via Casein Kinase 1-dependent Degradation of the Mammalian Period-1 (Per1) Proteinm* , 2005, Journal of Biological Chemistry.

[65]  Choogon Lee,et al.  Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms* , 2011, The Journal of Biological Chemistry.

[66]  U. Hegerl,et al.  Genome‐wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study , 2016, Journal of sleep research.

[67]  Ying Xu,et al.  Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome , 2005, Nature.

[68]  Christopher R. Jones,et al.  An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome , 2001, Science.

[69]  P. Colon The short and long of it--X rays. , 1974, Dental hygiene.

[70]  J. Takahashi,et al.  Central and peripheral circadian clocks in mammals. , 2012, Annual review of neuroscience.

[71]  C. Weitz,et al.  Specificity in circadian clock feedback from targeted reconstitution of the NuRD corepressor. , 2014, Molecular cell.

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

[73]  S. Kay,et al.  Time zones: a comparative genetics of circadian clocks , 2001, Nature Reviews Genetics.

[74]  Ueli Schibler,et al.  The loss of circadian PAR bZip transcription factors results in epilepsy. , 2004, Genes & development.

[75]  M. Rosbash,et al.  The Implications of Multiple Circadian Clock Origins , 2009, PLoS biology.

[76]  U. Schibler,et al.  The mammalian circadian timing system: organization and coordination of central and peripheral clocks. , 2010, Annual review of physiology.

[77]  J. Takahashi,et al.  Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals , 2012, Science.

[78]  E. Mignot,et al.  The Genetics of Narcolepsy , 2003 .

[79]  Shihoko Kojima,et al.  Circadian control of mRNA polyadenylation dynamics regulates rhythmic protein expression. , 2012, Genes & development.

[80]  H. Price Past and future , 1990, Nature.

[81]  Hanspeter Herzel,et al.  β-TrCP1-Mediated Degradation of PERIOD2 Is Essential for Circadian Dynamics , 2007, Journal of biological rhythms.

[82]  Erik D Herzog,et al.  Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons , 2005, Nature Neuroscience.

[83]  R. D. Rudic,et al.  Histone Acetyltransferase-dependent Chromatin Remodeling and the Vascular Clock* , 2004, Journal of Biological Chemistry.

[84]  Satchidananda Panda,et al.  Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. , 2012, Cell metabolism.

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

[86]  P. Hardin,et al.  Circadian rhythms from multiple oscillators: lessons from diverse organisms , 2005, Nature Reviews Genetics.

[87]  R. Young,et al.  A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells , 2007, Cell.

[88]  A. Sancar,et al.  Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock , 2014, Genes & development.

[89]  P. Elliott,et al.  A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk , 2009, Nature Genetics.

[90]  Giacomo Cavalli,et al.  Organization and function of the 3D genome , 2016, Nature Reviews Genetics.

[91]  Christopher R. Jones,et al.  Genetic basis of human circadian rhythm disorders , 2013, Experimental Neurology.

[92]  R. Evans,et al.  Cryptochromes mediate rhythmic repression of the glucocorticoid receptor , 2011, Nature.

[93]  D. Gatfield,et al.  Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames , 2015, Genome research.

[94]  M. Hughes,et al.  A circadian gene expression atlas in mammals: Implications for biology and medicine , 2014, Proceedings of the National Academy of Sciences.

[95]  Max A. Little,et al.  Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank , 2016, Nature Communications.

[96]  John T. Lis,et al.  Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans , 2012, Nature Reviews Genetics.

[97]  J. Bass,et al.  Circadian topology of metabolism , 2012, Nature.

[98]  M. Lazar,et al.  Clocks, metabolism, and the epigenome. , 2012, Molecular cell.

[99]  L. Miraglia,et al.  A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock , 2004, Neuron.

[100]  D. Bechtold,et al.  Setting Clock Speed in Mammals: The CK1ɛ tau Mutation in Mice Accelerates Circadian Pacemakers by Selectively Destabilizing PERIOD Proteins , 2008, Neuron.

[101]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[102]  C. Weitz,et al.  A Molecular Mechanism for Circadian Clock Negative Feedback , 2011, Science.

[103]  Inês Barroso,et al.  Variants in MTNR1B influence fasting glucose levels , 2009, Nature Genetics.

[104]  Alan L. Hutchison,et al.  Pancreatic β cell enhancers regulate rhythmic transcription of genes controlling insulin secretion , 2015, Science.

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

[106]  K Kume,et al.  Interacting molecular loops in the mammalian circadian clock. , 2000, Science.

[107]  Masamitsu Iino,et al.  System-level identification of transcriptional circuits underlying mammalian circadian clocks , 2005, Nature Genetics.

[108]  A. B. Reddy,et al.  Metabolic and nontranscriptional circadian clocks: eukaryotes. , 2014, Annual review of biochemistry.

[109]  Lan-fen Li,et al.  Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA , 2012, Cell Research.

[110]  James Taylor,et al.  Genomic approaches towards finding cis-regulatory modules in animals , 2012, Nature Reviews Genetics.

[111]  Post-transcriptional control of the mammalian circadian clock: implications for health and disease , 2016, Pflügers Archiv - European Journal of Physiology.

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

[113]  J. Lee,et al.  Circadian Clock, Cancer, and Chemotherapy , 2014, Biochemistry.

[114]  Ankur Roy,et al.  Circadian Enhancers Coordinate Multiple Phases of Rhythmic Gene Transcription In Vivo , 2014, Cell.

[115]  Achim Kramer,et al.  Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function , 2012, Proceedings of the National Academy of Sciences.

[116]  Rikuhiro G. Yamada,et al.  Delay in Feedback Repression by Cryptochrome 1 Is Required for Circadian Clock Function , 2011, Cell.

[117]  Samer Hattar,et al.  Light as a central modulator of circadian rhythms, sleep and affect , 2014, Nature Reviews Neuroscience.

[118]  A. B. Reddy,et al.  A clockwork web: circadian timing in brain and periphery, in health and disease , 2003, Nature Reviews Neuroscience.

[119]  Dirk Eick,et al.  Transcribing RNA Polymerase II Is Phosphorylated at CTD Residue Serine-7 , 2007, Science.

[120]  B. Tu,et al.  Metabolic cycles as an underlying basis of biological oscillations , 2006, Nature Reviews Molecular Cell Biology.

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

[122]  Michael B. Stadler,et al.  Analysis of intronic and exonic reads in RNA-seq data characterizes transcriptional and post-transcriptional regulation , 2015, Nature Biotechnology.

[123]  Andres Metspalu,et al.  Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci , 2016, PLoS genetics.

[124]  Aziz Sancar,et al.  Biochemical Analysis of the Canonical Model for the Mammalian Circadian Clock* , 2011, The Journal of Biological Chemistry.

[125]  Weiman Xing,et al.  Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase , 2013, Cell Research.

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

[127]  A. Chawla,et al.  Circadian Gene Bmal1 Regulates Diurnal Oscillations of Ly6Chi Inflammatory Monocytes , 2013, Science.

[128]  B. O’Malley,et al.  Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude via REV-ERB Loading. , 2015, Molecular cell.

[129]  Yi Liu,et al.  Mechanism of the Neurospora Circadian Clock, a FREQUENCY-centric View , 2014, Biochemistry.

[130]  C. Scheiermann,et al.  Circadian control of the immune system , 2013, Nature Reviews Immunology.

[131]  M. Tyers,et al.  Transcriptional regulation: Kamikaze activators , 2000, Current Biology.

[132]  Michele Pagano,et al.  SCFFbxl3 Ubiquitin Ligase Targets Cryptochromes at Their Cofactor Pocket , 2013, Nature.

[133]  P. Froguel,et al.  The Difficult Journey from Genome-wide Association Studies to Pathophysiology: The Melatonin Receptor 1B (MT2) Paradigm. , 2016, Cell Metabolism.

[134]  M. Lazar,et al.  Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock , 2015, Science.

[135]  Michael W Young,et al.  Interactive features of proteins composing eukaryotic circadian clocks. , 2014, Annual review of biochemistry.

[136]  Steven M. Reppert,et al.  Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock , 2009, Molecular and Cellular Biology.

[137]  Paolo Sassone-Corsi,et al.  Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription , 2014, Proceedings of the National Academy of Sciences.

[138]  D. P. King,et al.  Role of the CLOCK protein in the mammalian circadian mechanism. , 1998, Science.

[139]  C. Weitz,et al.  Feedback Regulation of Transcriptional Termination by the Mammalian Circadian Clock PERIOD Complex , 2012, Science.

[140]  T. Jacks,et al.  Circadian Rhythm Disruption Promotes Lung Tumorigenesis. , 2016, Cell metabolism.

[141]  Yichi Xu,et al.  Long-Range Chromosome Interactions Mediated by Cohesin Shape Circadian Gene Expression , 2016, PLoS genetics.

[142]  D. Altshuler,et al.  Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion , 2009, Nature Genetics.

[143]  A. Loudon,et al.  Tuning the Period of the Mammalian Circadian Clock: Additive and Independent Effects of CK1εTau and Fbxl3Afh Mutations on Mouse Circadian Behavior and Molecular Pacemaking , 2011, The Journal of Neuroscience.

[144]  Felix Naef,et al.  Genome-Wide and Phase-Specific DNA-Binding Rhythms of BMAL1 Control Circadian Output Functions in Mouse Liver , 2011, PLoS biology.

[145]  Ravi Allada,et al.  Circadian organization of behavior and physiology in Drosophila. , 2010, Annual review of physiology.

[146]  Peter C. St. John,et al.  Identification of Small Molecule Activators of Cryptochrome , 2012, Science.

[147]  M. Rosbash,et al.  Dynamic PER repression mechanisms in the Drosophila circadian clock: from on-DNA to off-DNA. , 2010, Genes & development.

[148]  Steven A. Brown,et al.  PERIOD1-Associated Proteins Modulate the Negative Limb of the Mammalian Circadian Oscillator , 2005, Science.

[149]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[150]  Hiroshi Kori,et al.  Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus , 2011, Nature communications.

[151]  Steven M. Reppert,et al.  Rhythmic histone acetylation underlies transcription in the mammalian circadian clock , 2003, Nature.

[152]  P. Sassone-Corsi,et al.  Circadian clocks, epigenetics, and cancer , 2015, Current opinion in oncology.

[153]  Satchidananda Panda,et al.  Histone Lysine Demethylase JARID1a Activates CLOCK-BMAL1 and Influences the Circadian Clock , 2011, Science.

[154]  Jared Rutter,et al.  Metabolism and the control of circadian rhythms. , 2002, Annual review of biochemistry.

[155]  L. Mirny,et al.  The 3D Genome as Moderator of Chromosomal Communication , 2016, Cell.

[156]  C. Green,et al.  Circadian Genomics Reveal a Role for Post-transcriptional Regulation in Mammals , 2014, Biochemistry.

[157]  Leighton J. Core,et al.  Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters , 2008, Science.

[158]  Ryan A. Flynn,et al.  A unique chromatin signature uncovers early developmental enhancers in humans , 2011, Nature.

[159]  D. Gatfield,et al.  MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale , 2014, eLife.

[160]  Seung-Hee Yoo,et al.  Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism. , 2009, Molecular cell.

[161]  T. Takagi,et al.  CLOCK-Controlled Polyphonic Regulation of Circadian Rhythms through Canonical and Noncanonical E-Boxes , 2014, Molecular and Cellular Biology.

[162]  Tao Liu,et al.  A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism , 2011, Science.

[163]  T. Möröy,et al.  Rhythmic U2af26 alternative splicing controls PERIOD1 stability and the circadian clock in mice. , 2014, Molecular cell.

[164]  P. Sassone-Corsi,et al.  NAD+-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1 , 2015, Nature Structural &Molecular Biology.

[165]  M. Rosbash,et al.  CLOCK:BMAL1 is a pioneer-like transcription factor , 2014, Genes & development.

[166]  P. Pévet,et al.  Melatonin: Both master clock output and internal time-giver in the circadian clocks network , 2011, Journal of Physiology-Paris.

[167]  Steven M Reppert,et al.  mCRY1 and mCRY2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop , 1999, Cell.

[168]  Youngchang Kim,et al.  Structural integration in hypoxia-inducible factors , 2015, Nature.

[169]  P. Sassone-Corsi,et al.  Metabolism and the circadian clock converge. , 2013, Physiological reviews.

[170]  Andrew D. Johnson,et al.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study , 2014, Molecular Psychiatry.

[171]  Satchidananda Panda,et al.  Regulation of Circadian Behavior and Metabolism by Rev-erbα and Rev-erbβ , 2012, Nature.

[172]  Ueli Schibler,et al.  Blood-Borne Circadian Signal Stimulates Daily Oscillations in Actin Dynamics and SRF Activity , 2013, Cell.

[173]  M. Rapé,et al.  Better Safe than Sorry: Interlinked Feedback Loops for Robust Mitophagy. , 2015, Molecular cell.

[174]  David K Welsh,et al.  Suprachiasmatic nucleus: cell autonomy and network properties. , 2010, Annual review of physiology.

[175]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[176]  J. Takahashi,et al.  Mammalian circadian biology: elucidating genome-wide levels of temporal organization. , 2004, Annual review of genomics and human genetics.

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

[178]  Dalei Wu,et al.  Structural characterization of mammalian bHLH-PAS transcription factors. , 2017, Current opinion in structural biology.

[179]  Stephen Smale,et al.  Functional organization of the human 4D Nucleome , 2015, Proceedings of the National Academy of Sciences.

[180]  N. Eriksson,et al.  GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person , 2016, Nature Communications.

[181]  R. Ligrone Eukaryotes , 2019, Biological Innovations that Built the World.

[182]  Hong Zhang,et al.  Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex , 2012, Science.

[183]  J. Takahashi,et al.  Finding New Clock Components: Past and Future , 2004, Journal of biological rhythms.

[184]  Akinobu Suzuki,et al.  CBP/p300 is a cell type-specific modulator of CLOCK/BMAL1-mediated transcription , 2009, Molecular Brain.

[185]  Inês Barroso,et al.  Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes , 2012, Nature Genetics.

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

[187]  Joseph S. Takahashi,et al.  A tunable artificial circadian clock in clock-defective mice , 2015, Nature Communications.

[188]  N. Guex,et al.  Genome-Wide RNA Polymerase II Profiles and RNA Accumulation Reveal Kinetics of Transcription and Associated Epigenetic Changes During Diurnal Cycles , 2012, PLoS biology.

[189]  Erin L. McDearmon,et al.  The genetics of mammalian circadian order and disorder: implications for physiology and disease , 2008, Nature Reviews Genetics.

[190]  J. Takahashi,et al.  Phosphorylation of LSD1 by PKCα is crucial for circadian rhythmicity and phase resetting. , 2014, Molecular cell.

[191]  Özkan Yildiz,et al.  Structural and Functional Analyses of PAS Domain Interactions of the Clock Proteins Drosophila PERIOD and Mouse PERIOD2 , 2009, PLoS biology.

[192]  A. Kramer,et al.  Interaction of Circadian Clock Proteins CRY1 and PER2 Is Modulated by Zinc Binding and Disulfide Bond Formation , 2014, Cell.

[193]  J. Takahashi,et al.  Genetics of circadian rhythms in Mammalian model organisms. , 2011, Advances in genetics.

[194]  Y. Fukada,et al.  FBXL21 Regulates Oscillation of the Circadian Clock through Ubiquitination and Stabilization of Cryptochromes , 2013, Cell.

[195]  L. Spriet,et al.  implications for health and disease Triacylglycerol lipases and metabolic control , 2016 .

[196]  Ueli Schibler,et al.  System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock , 2007, PLoS biology.

[197]  Ueli Schibler,et al.  Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals. , 2015, Cold Spring Harbor symposia on quantitative biology.