title: A mammalian circadian clock model incorporating daytime expression elements.
abstract: Models of the mammalian clock have traditionally been based around two feedback loops-the self-repression of Per/Cry by interfering with activation by BMAL/CLOCK, and the repression of Bmal/Clock by the REV-ERB proteins. Recent experimental evidence suggests that the D-box, a transcription factor binding site associated with daytime expression, plays a larger role in clock function than has previously been understood. We present a simplified clock model that highlights the role of the D-box and illustrate an approach for finding maximum-entropy ensembles of model parameters, given experimentally imposed constraints. Parameter variability can be mitigated using prior probability distributions derived from genome-wide studies of cellular kinetics. Our model reproduces predictions concerning the dual regulation of Cry1 by the D-box and Rev-ErbA/ROR response element (RRE) promoter elements and allows for ensemble-based predictions of phase response curves (PRCs). Nonphotic signals such as Neuropeptide Y (NPY) may act by promoting Cry1 expression, whereas photic signals likely act by stimulating expression from the E/E' box. Ensemble generation with parameter probability restraints reveals more about a model's behavior than a single optimal parameter set.
authors.affiliation: Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Jolley
authors.affiliation: Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Ukai-Tadenuma
authors.affiliation: Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Perrin
authors.affiliation: Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Department of Biological Sciences, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan; Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Systems Pharmacology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address: uedah-tky@umin.ac.jp.
authors.forename: Hiroki R
authors.initials: HR
authors.lastname: Ueda
mesh_terms: D000818:Animals; D057906:Circadian Clocks; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D008954:Models, Biological; D049490:Systems Biology
chemical_list: D056925:Circadian Rhythm Signaling Peptides and Proteins