A model of the cell-autonomous mammalian circadian clock.
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.
Mirsky
Henry P
HP
Program in Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106-9611, USA.
Liu
Andrew C
AC
Welsh
David K
DK
Kay
Steve A
SA
Doyle
Francis J
FJ
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007700:Kinetics; D008322:Mammals / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D005420:Flavoproteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; C538944:Clock protein, mouse