1. ICS280 Homework 1 –Due Thursday Jan 16 Read 2 of the 4 review articles Get software

2. DNA (+ bound proteins) Transcription to mRNA; Translation to protein Protein (MyoD) Regulation of DNA transcription by proteins (transcription factors) mRNA Structures, motors, sensors, effectors, feedback circuitry,... DNA  RNA  Protein  Gene Regulation (DNA)

3. Gene Expression Data: Immunofluorescence hunchback and Kruppel with nuclear mask (Kosman, Reinitz, Sharp PSB 1998)

4. Gene Expression Data: Immunofluorescence Drosophila gap and pair-rule gene expression as protein. Green: Kruppel. Blue: giant. Red: even-skipped. Courtesy John Reinitz.

5. Gene Gene Expression Clusters - C. Elegans

6. Transcriptional Gene Regulation Networks Is oversimplified by mass-action kinetics Gene Regulation Network (GRN) model Drosophila eve stripe expression in model (right) and data (left). Green: eve expression, red: kni expression. From [Reinitz and Sharp, Mech. of Devel., 49:133-158, 1995 ]. [Mjolsness et al. J. Theor. Biol. 152: 429-453, 1991]

8. Fletcher et al., Science v. 283, 1999 Brand et. al., Science 289, 617-619, (2000) WUS

10. Meristem Simulation

11. Repressilator

13. Eukaryotic Cell Cycle - Schematic J. Tyson and B. Novak, J. theor. Biol. (2001) 210, 249}263

14. Cell Cycle Protein Interactions J. Tyson and B. Novak, J. theor. Biol. (2001) 210, 249}263

16. Cell Simulation Software CELLERATOR interactive biological model description Systems Biology Markup Language model SBML model SBML CELL MODEL READER SOLUTION/ OPTIMIZATION ENGINE CODE WRITER templates LA code (C++) observed data annealer state parameters SOLVER/OPTMIZER FOR THE CELL MODEL model parameters SBML model OTHER APPLICATIONS FOR SBML MODELS... DIMENSION REDUCTION Biological Hypotheses Datasets Regulations and reactions Mathematical model generation Simulation Mining Simulation results Followup experiments Optimization Biology User

17. MAP Kinase Pathways in Solution INPUT OUTPUT

18. Cellerator Demo

19. Cellerator: Automatic Model Generation

20. Model Generation and Use Solver Output Canonical Form System of ODEs Input Canonical Form Biochemical Notation Concentrations vs. Time Activity (e.g., Cell Division) A B C

21. E.g. MAP Kinase Cascade With A. Levchenko J. Ferrell model w/o scaffold

22. Cellerator Arrow Translation

23. Elementary Reactions Bimolecular in solution: –A, B  {C} –Example: Yeast Fus3 phosphorylates Far1, arrests cell cycle. FUS3, KSS1 also phosphorylate Ste12 TF/Dig1/Dig2, leads to mating Binding/unbinding at a site: –A, S  S-A –Example: Swi5p binds to DNA e.g. UTR for HO, responsible for mating type switch in daughter yeast cells.

24. SWI5 details –Dephosphorylation of Swi5 by cdc14p is instrumental in up-regulating Sic1p level which leads to M progression [MIPS, BJW notes] –Nuclear localization (NLS) sequence is normally phosphorylated in S, G2, and M when Swi5p is located in the cytoplasm, and dephosphorylated during G1 when Swi5p enters the nucleus. Phosphorylation of the NLS is catalyzed by the B cyclin kinase. Three serines phosphorylated by cdc28p in vitro [MIPS] –Pho2p-Swi5p-DNA ternary complex is significantly more stable (t[1/2] = 20 min) than either Pho2p-DNA (t[1/2] = 2 min) or Swi5p-DNA (t[1/2] = 15 sec) binary complexes [BJW notes]

25. Transcription Factor Binding Note: n=2 homodimer cooperativity coefficient both amplifies and suppresses signals. Heterodimers increase specificity.

26. TF Activation before Binding

27. Mass Action Kinetics Law of mass action for dilute solution in equilibrium: Applied to bimolecular “prereaction” interactions:

28. Cellerator Arrows: Catalytic Reactions  

29. Cellerator Arrows: Transcriptional Regulation

30. MAPK Pathways in Saccharomyces cerevisiae http://www.genome.ad.jp/kegg/

31. MAPK cascades Madhani, HD. Fink, GR. THE RIDDLE OF MAP KINASE SIGNALING SPECIFICITY [Review]. Trends in Genetics. 14(4):151-155, 1998 Apr.

32. KEGG yeast cell cycle

33. GO hierarchy for Molecular Function:Transcription Factor Source: SGD

34. Sigmoid Reaction Schema in UML

35. Sigmoid Reactant Schema in UML

36. Sigmoid Knowledge Source, Model Schemata

37. Reactions DB Bioinformatics Software Architecture MLX Analyses - Clustering - Classification - Cross-validation - Scoring - Gene list tools Regulatory Cell Models Cellerator, SBML Expression DB - MAGE-OM + mods - Genex - FGDB conversion Python/Java/CORBA Image DB - MLX image classes - Diamond Eye (JPL) Sequence DB GUI - Genespring - Mimir - (Genetrix, others?)

38. Current Cellerator Library Myogenesis (Chris Hart) CMX Mitotic Oscillator (Goldbeter) Repressilator (Elowitz & Leibler) IP3 Calcium Channel (DeYoung & Keizer) MAPK on Scaffold Cell Cycle (Novak & Tyson) Glycolysis (Sel’kov) Ring Oscillator (enzymatic or transcriptional) Meristem (in progress) Hematopoietic Differentiation (in progress; includes C/EPB; PU.1; GATA-1; AML1; CBF;NFKB; CSFR)

40. Cellerator Canonical Forms in Everyday Language Input: Arrows + IC + rates (Palette Driven) –Mass action –Enzymatic –Transcriptional –Cascades –Modules (e.g., MAPK) Intermediate Output –simple chemical reactions (where appropriate) Output - ODES –Mathematica equations, SBML, C, FORTRAN, HTML, MATHML, XML –Optional Numerical Solution + Plots

41. Cellerator Arrows: Law of Mass Action  