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A model of the cell-autonomous mammalian circadian clock

Academic Article
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Overview

authors

  • Mirsky, H. P.
  • Liu, A. C.
  • Welsh, D. K.
  • Kay, Steve A.
  • Doyle III, F. J.

publication date

  • July 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Circadian timekeeping by intracellular molecular clocks is evident widely in prokaryotes and eukaryotes. The clockworks are driven by autoregulatory feedback loops that lead to oscillating levels of components whose maxima are in fixed phase relationships with one another. These phase relationships are the key metric characterizing the operation of the clocks. In this study, we built a mathematical model from the regulatory structure of the intracellular circadian clock in mice and identified its parameters using an iterative evolutionary strategy, with minimum cost achieved through conformance to phase separations seen in cell-autonomous oscillators. The model was evaluated against the experimentally observed cell-autonomous circadian phenotypes of gene knockouts, particularly retention of rhythmicity and changes in expression level of molecular clock components. These tests reveal excellent de novo predictive ability of the model. Furthermore, sensitivity analysis shows that these knockout phenotypes are robust to parameter perturbation.

subject areas

  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Biological Clocks
  • CLOCK Proteins
  • Cell Cycle Proteins
  • Circadian Rhythm
  • Cryptochromes
  • Flavoproteins
  • Gene Expression Regulation
  • Kinetics
  • Mammals
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nuclear Proteins
  • Period Circadian Proteins
  • Phenotype
  • RNA, Messenger
  • Reproducibility of Results
  • Time Factors
  • Trans-Activators
  • Transcription Factors
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Research

keywords

  • cell-level model
  • evolutionary strategy
  • gene regulatory network
  • mathematical model
  • mouse
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Identity

PubMed Central ID

  • PMC2699375

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0904837106

PubMed ID

  • 19549830
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Additional Document Info

start page

  • 11107

end page

  • 11112

volume

  • 106

issue

  • 27

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