The Interplay of cis-Regulatory Elements Rules Circadian Rhythms in Mouse Liver

The mammalian circadian clock is driven by cell-autonomous transcriptional feedback loops that involve E-boxes, D-boxes, and ROR-elements. In peripheral organs, circadian rhythms are additionally affected by systemic factors. We show that intrinsic combinatorial gene regulation governs the liver clock. With a temporal resolution of 2 h, we measured the expression of 21 clock genes in mouse liver under constant darkness and equinoctial light-dark cycles. Based on these data and known transcription factor binding sites, we develop a six-variable gene regulatory network. The transcriptional feedback loops are represented by equations with time-delayed variables, which substantially simplifies modelling of intermediate protein dynamics. Our model accurately reproduces measured phases, amplitudes, and waveforms of clock genes. Analysis of the network reveals properties of the clock: overcritical delays generate oscillations; synergy of inhibition and activation enhances amplitudes; and combinatorial modulation of transcription controls the phases. The agreement of measurements and simulations suggests that the intrinsic gene regulatory network primarily determines the circadian clock in liver, whereas systemic cues such as light-dark cycles serve to fine-tune the rhythms.

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

[2]  S. Hashimoto,et al.  Identification of functional clock-controlled elements involved in differential timing of Per1 and Per2 transcription , 2010, Nucleic acids research.

[3]  Christopher R. Jones,et al.  Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2 , 2007, Cell.

[4]  P. Chan,et al.  Chronobiological Analysis of Circadian Patterns in Transcription of Seven Key Clock Genes in Six Peripheral Tissues in Mice , 2007, Chronobiology international.

[5]  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.

[6]  S. Panda,et al.  Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression , 2009, Proceedings of the National Academy of Sciences.

[7]  Masaru Tomita,et al.  Positive Autoregulation Delays the Expression Phase of Mammalian Clock Gene Per2 , 2011, PloS one.

[8]  Steve A. Kay,et al.  SnapShot: Circadian Clock Proteins , 2008, Cell.

[9]  U. Schibler,et al.  Expression of the liver-enriched transcriptional activator protein DBP follows a stringent circadian rhythm , 1990, Cell.

[10]  A. Kohsaka,et al.  The clockwork of metabolism. , 2007, Annual review of nutrition.

[11]  D. Bechtold,et al.  Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes , 2010, Proceedings of the National Academy of Sciences.

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

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

[14]  Terence Hwa,et al.  Transcriptional regulation by the numbers: models. , 2005, Current opinion in genetics & development.

[15]  Andrew I. Su,et al.  A Genome-wide RNAi Screen for Modifiers of the Circadian Clock in Human Cells , 2009, Cell.

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

[17]  Caroline C. Friedel,et al.  Conserved principles of mammalian transcriptional regulation revealed by RNA half-life , 2009, Nucleic acids research.

[18]  Kai-Florian Storch,et al.  Extensive and divergent circadian gene expression in liver and heart , 2002, Nature.

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

[20]  T. Kawamoto,et al.  Dec1 and Dec2 are regulators of the mammalian molecular clock , 2002, Nature.

[21]  Jure Acimovic,et al.  Determination of reference genes for circadian studies in different tissues and mouse strains , 2010, BMC Molecular Biology.

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

[23]  Yoh Iwasa,et al.  Comparative study of circadian clock models, in search of processes promoting oscillation. , 2002, Journal of theoretical biology.

[24]  Ueli Schibler,et al.  Circadian rhythms: mechanisms and therapeutic implications. , 2007, Annual review of pharmacology and toxicology.

[25]  Takeya Kasukawa,et al.  Proof-by-synthesis of the transcriptional logic of mammalian circadian clocks , 2008, Nature Cell Biology.

[26]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

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

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

[29]  Y Sakaki,et al.  Resetting central and peripheral circadian oscillators in transgenic rats. , 2000, Science.

[30]  Daniel B. Forger,et al.  A detailed predictive model of the mammalian circadian clock , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Sumio Sugano,et al.  A transcription factor response element for gene expression during circadian night , 2002, Nature.

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

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

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

[35]  Nacho Molina,et al.  Mammalian Genes Are Transcribed with Widely Different Bursting Kinetics , 2011, Science.

[36]  Achim Kramer,et al.  Tuning the Mammalian Circadian Clock: Robust Synergy of Two Loops , 2011, PLoS Comput. Biol..

[37]  Szymon M. Kielbasa,et al.  Regulation of Clock-Controlled Genes in Mammals , 2009, PloS one.

[38]  Haruhiko Soma,et al.  Transcriptional oscillation of canonical clock genes in mouse peripheral tissues , 2004, BMC Molecular Biology.

[39]  Steve A. Kay,et al.  Redundant Function of REV-ERBα and β and Non-Essential Role for Bmal1 Cycling in Transcriptional Regulation of Intracellular Circadian Rhythms , 2008, PLoS genetics.

[40]  M. Mackey,et al.  Modelling transcriptional feedback loops: the role of Gro/TLE1 in Hes1 oscillations , 2006, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[41]  F. Tamanini,et al.  Flexible phase adjustment of circadian albumin D site-binding protein (DBP) gene expression by CRYPTOCHROME1. , 2010, Genes & development.

[42]  A. Goldbeter,et al.  Toward a detailed computational model for the mammalian circadian clock , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Michael Unser,et al.  Circadian gene expression is resilient to large fluctuations in overall transcription rates , 2009, The EMBO journal.

[44]  L. Glass,et al.  Oscillation and chaos in physiological control systems. , 1977, Science.

[45]  A. Atwood,et al.  Cell-autonomous circadian clock of hepatocytes drives rhythms in transcription and polyamine synthesis , 2011, Proceedings of the National Academy of Sciences.

[46]  Steven A. Brown,et al.  Molecular insights into human daily behavior , 2008, Proceedings of the National Academy of Sciences.

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

[48]  Hanspeter Herzel,et al.  Coupling governs entrainment range of circadian clocks , 2010, Molecular systems biology.

[49]  Systems biology of mammalian circadian clocks. , 2010, Annual review of physiology.

[50]  J. Takahashi,et al.  Molecular components of the mammalian circadian clock. , 2006, Human molecular genetics.

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

[52]  C. Pennartz,et al.  A Mathematical Model for the Intracellular Circadian Rhythm Generator , 1999, The Journal of Neuroscience.

[53]  Paul I. Barton,et al.  The Per2 Negative Feedback Loop Sets the Period in the Mammalian Circadian Clock Mechanism , 2007, PLoS Comput. Biol..

[54]  Hanspeter Herzel,et al.  Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). , 2006, Genes & development.

[55]  D. A. Baxter,et al.  Modeling Circadian Oscillations with Interlocking Positive and Negative Feedback Loops , 2001, The Journal of Neuroscience.

[56]  Alexei A. Sharov,et al.  Database for mRNA Half-Life of 19 977 Genes Obtained by DNA Microarray Analysis of Pluripotent and Differentiating Mouse Embryonic Stem Cells , 2008, DNA research : an international journal for rapid publication of reports on genes and genomes.

[57]  Richard E. Kronauer,et al.  Plasticity of the Intrinsic Period of the Human Circadian Timing System , 2007, PloS one.

[58]  S. Jacobshagen,et al.  At Least Four Distinct Circadian Regulatory Mechanisms Are Required for All Phases of Rhythms in mRNA Amount , 2008, Journal of biological rhythms.

[59]  H. Westerhoff,et al.  Recurrent design patterns in the feedback regulation of the mammalian signalling network , 2008, Molecular systems biology.

[60]  Peter Ruoff,et al.  Semi-algebraic optimization of temperature compensation in a general switch-type negative feedback model of circadian clocks , 2007, Journal of mathematical biology.

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