Effective models of periodically driven networks.

Circadian rhythms are governed by a highly coupled, complex network of genes. Due to feedback within the network, any modification of the system's state requires coherent changes in several nodes. A model of the underlying network is necessary to compute these modifications. We use an effective modeling approach for this task. Rather than inferred biochemical interactions, our method utilizes microarray data from a group of mutants for its construction. With simulated data, we develop an effective model for a circadian network in a peripheral tissue, subject to driving by the suprachiasmatic nucleus, the mammalian pacemaker. The effective network can predict time-dependent gene expression levels in other mutants.

[1]  Marc Timme,et al.  Inferring network topology from complex dynamics , 2010, 1007.1640.

[2]  Maqc Consortium The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements , 2006, Nature Biotechnology.

[3]  Andrei Török,et al.  Using Effective Subnetworks to Predict Selected Properties of Gene Networks , 2010, PloS one.

[4]  Judit Zámborszky,et al.  Computational Analysis of Mammalian Cell Division Gated by a Circadian Clock: Quantized Cell Cycles and Cell Size Control , 2007, Journal of biological rhythms.

[5]  E. Meyer-Bernstein,et al.  Differential serotonergic innervation of the suprachiasmatic nucleus and the intergeniculate leaflet and its role in circadian rhythm modulation , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[6]  M. Merrow,et al.  The Network of Time: Understanding the Molecular Circadian System , 2003, Current Biology.

[7]  I. N. Karatsoreos,et al.  Chronobiology: biological timekeeping , 2004, Physiology & Behavior.

[8]  L. Fu,et al.  The circadian clock: pacemaker and tumour suppressor , 2003, Nature Reviews Cancer.

[9]  S. Yamaguchi,et al.  Control Mechanism of the Circadian Clock for Timing of Cell Division in Vivo , 2003, Science.

[10]  M. Cross,et al.  Pattern formation outside of equilibrium , 1993 .

[11]  M. Hastings,et al.  Circadian clockwork: two loops are better than one , 2000, Nature Reviews Neuroscience.

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

[13]  G. Kuhn,et al.  Circadian rhythm, shift work, and emergency medicine. , 2001, Annals of emergency medicine.

[14]  Andrew J. Millar,et al.  The Contributions of Interlocking Loops and Extensive Nonlinearity to the Properties of Circadian Clock Models , 2010, PloS one.

[15]  J. Collins,et al.  Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling , 2003, Science.

[16]  Michael J. McDonald,et al.  Microarray Analysis and Organization of Circadian Gene Expression in Drosophila , 2001, Cell.

[17]  V. Ambros The functions of animal microRNAs , 2004, Nature.

[18]  A. Goldbeter A model for circadian oscillations in the Drosophila period protein (PER) , 1995, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[19]  J. Lehár,et al.  Multi-target therapeutics: when the whole is greater than the sum of the parts. , 2007, Drug discovery today.

[20]  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.

[21]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[22]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[23]  G. Gill,et al.  Regulation of the initiation of eukaryotic transcription. , 2001, Essays in biochemistry.

[24]  H. Kitano A robustness-based approach to systems-oriented drug design , 2007, Nature Reviews Drug Discovery.

[25]  Markus Meister,et al.  Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms , 1995, Neuron.

[26]  David Spiegel,et al.  Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease? , 2003, Brain, Behavior, and Immunity.

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

[28]  M. Gerstein,et al.  Structure and evolution of transcriptional regulatory networks. , 2004, Current opinion in structural biology.

[29]  Xiang-Dong Fu,et al.  Timing of plant immune responses by a central circadian regulator , 2011, Nature.