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Supporting Document Bayesian Experts in Exploring Reaction Kinetics of Transcription Circuits

Supporting Document Bayesian Experts in Exploring Reaction Kinetics of Transcription Circuits. - On Transcriptional Circuit Model for Mammalian Circadian Clock -. Yoshida, R., Saito, M.M., Nagao, H. and Higuchi, T. The Institute of Statistical Mathematics, ROIS.

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Supporting Document Bayesian Experts in Exploring Reaction Kinetics of Transcription Circuits

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  1. Supporting Document Bayesian Experts in Exploring Reaction Kinetics of Transcription Circuits - On Transcriptional Circuit Model for Mammalian Circadian Clock - Yoshida, R., Saito, M.M., Nagao, H. and Higuchi, T. The Institute of Statistical Mathematics, ROIS

  2. Mammalian Clock and Clock-Controlled Genes in the Model According to the TF promoter analysis of Ueda et al. (2005), we have developed a model on transcription factor regulatory networks, involving 19 clock-related state variables in below: Clock Bmal1 (Arntl or Mop3) Per1 Per2 Cry1 RevErbA α (Nr1d1) Rora (Ror αlpha) Dbp Helix-loop-helix-PAS transcription factors Clock-Regulating 8 Transcription Factors Orphan nuclear hormone receptors bZip-family (transcription factor) clock bmal1 (arntl or mop3) per1 per2 cry1 revErbA α (nr1d1) rora (ror αlpha) dbp 8 mRNAs Clock/Bmal1 Per1/Cry1 Per2/Cry1 3 TF complexes

  3. Network Diagram of the Transcriptional Circuits (Hybrid Functional Petri Net) All the diagrams relevant to the baseline and degradation are omitted. dbp Dbp per1 Per1 clock Clock Per1/Cry1 per2 Per2 Bmal1/Clock bmal1 Bmal1 Per2/Cry1 cry1 Cry1 Rev-ErbA α rev-erbA α Ror(a) ror(a) Normal arc Test arc Inhibitory arc Continuous place Transition

  4. The Mathematical Form of ODE Model The circuit model describes a regulatory mechanism of the endogenous variables based on the following 19 ODEs. Notations involving mRNA mRNA RRE E/E’ box D box Three types of regulatory elements in promoters Notations involving Protein and Protein Complex Protein or Protein complex RRE E/E’ box D box TF binding sites on promoters A R Activators or Inhibitor?

  5. The Mathematical Form of ODE Model Variable: per1;Description: Transcription; Variable ID: 1 Regulatory elements in promoter: E/E’ box, D box Activators: Bmal1/Clock, Dbp Inhibitors: Per1/Cry1, Per2/Cry2 E/E’ box D box Variable : per2;Description: Transcription; Variable ID: 2 Regulatory elements in promoter: E/E’ box, D box Activators: Bmal1/Clock, Dbp, Npas2 Inhibitors: Per1/Cry1, Per2/Cry2, Per3, Dec1 E/E’ box D box

  6. The Mathematical Form of ODE Model Variable: cry1;Description: Transcription; Variable ID: 3 Regulatory elements in promoter: E/E’ box, RRE Activators: Bmal1/Clock, Rora, Inhibitors: Per1/Cry1, Per2/Cry2, Rev/ErbA E/E’ box RRE Variable: rev/erbA;Description: Transcription; Variable ID: 4 Regulatory elements in promoter: E/E’ box D box Activators: Bmal1/Clock, Dbp Inhibitors: Per1/Cry1, Per2/Cry1 E/E’ box D box

  7. The Mathematical Form of ODE Model Variable: rora;Description: Transcription; Variable ID: 5 Regulatory elements in promoter: D box Activators: Dbp Inhibitors: D box Variable: clock;Description: Transcription; Variable ID: 6 Regulatory elements in promoter: RRE Activators: Rora Inhibitors: Rev/ErbA RRE

  8. The Mathematical Form of ODE Model Variable: bmal1;Description: Transcription; Variable ID: 7 Regulatory elements in promoter: RRE Activators: Rora, Per1/Cry1, Per2/Cry1 Inhibitors:, Rev/ErbA RRE Variable: dec1;Description: Transcription; Variable ID: 8 Regulatory elements in promoter: E/E’box Activators: Bmal1/Clock Inhibitors: Per1/Cry1, Per2/Cry2 E/E’ box

  9. The Mathematical Form of ODE Model Variable: Per1;Description: Translation, Biding; Variable ID: 9 Bind to: Cry1 Bind Variable : Per2;Description: Translation, Binding; Variable ID: 10 Bind to: Cry1 Bind Variable: Cry1;Description: Translation, Binding; Variable ID: 11 Bind to: Per1, Per2 Bind Variable: Rev/ErbA;Description: Translation; Variable ID: 12 R RRE

  10. The Mathematical Form of ODE Model Variable: Clock;Description: Translation, Binding; Variable ID: 13 Bind to: Bmal1 Bind Variable: Bmal1;Description: Translation; Variable ID: 14 Bind to: Clock Bind Variable: Rora;Description: Translation; Variable ID: 15 A RRE Variable: Dbp;Description: Translation, Biding; Variable ID: 16 A D box

  11. The Mathematical Form of ODE Model Variable: Per1/Cry1;Description: Binding; Variable ID: 17 R E/E’ box Variable: Per2/Cry1;Description: Binding; Variable ID: 18 R E/E’ box Variable: Bmal1/Clock;Description: Binding; Variable ID: 19 A E/E’ box

  12. A Principle of Transcriptional Activities in Circadian Clocks Order of increase in daily transcriptional activities. Each gene is first categorized into the three elements (in rows) according to its target binding element, and further classified (in columns) according to its regulatory elements (combinations of the three regulatory sequences). Ueda et al., Nature Genetics, 2005 about 24 hours E/E’ box E/E’ box RRE E/E’ box D box RRE D box RRE Set of genes binding to E/E’ box elements in promoters (purple: repressors; green: activators) Clock Per1 Bhlhb2 Per3 Cry1 Npas2 E/E’ box Bhlhb3 Per2 Bmal1 Set of genes binding to D box elements in promoters (purple: repressors; green: activators) Nfil3 Dbp D box Set of genes binding to RRE elements in promoters (purple: repressors; green: activators) RevErbAα Rora Rorc RRE Nr1d2 Rorb

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