1. Network Dynamics of Budding Yeast Cell Cycle Supervisor: Dr. Lei-han Tang Presented by Cai Chunhui April 16, 2005

2. Presentation Outline  Introduction to budding yeast cell cycle  Budding Yeast Cell Cycle Control  Tang Chao’s model  Transcriptional regulation network  Further work

3. Introduction Yeast Cell Cycle  G1:Cell grows and enter the cell cycle  S: Bud emerges and cell duplicate its DNA  G2: Preparation for mitosis  M: Replicated DNA is segregated into mother cell and daughter cell.

4. Yeast Cell Cycle Control Yeast Cell Cycle is tightly regulated by cell cycle control system  A clock, or timer, that turns on each event at a specific time, and provide a relatively fixed amount of time for the completion of each event;  A mechanism for initiating events in correct order;  A mechanism to ensure that each event is triggered only once per cycle;  Binary (on/off) switch that trigger events in a complete, irreversible fashion;  Robustness, backup mechanism;  Adaptability.

5. Yeast Cell Cycle Control Yeast Cell-cycle Control System is based on  The activity of the cyclin-dependent kinase (CDK) Cdc28.  Gene regulation.

6. Yeast Cell Cycle Control Much is known about Ccd28 activities and it function when associated with different cyclins. ---- i.e. Cln2/Cdc28, Clb5/Cdc28, Clb2/Cdc28. synthesis degradation MPF synthesis degradation SPF

7. Yeast Cell Cycle Control Gene Regulation is poorly understand -- ~800 out of 6126 genes oscillate during cell cycle, with unknown functions of most genes

8. Yeast Cell Cycle Control Literature Database and source:  http://genome-www5.stanford.edu/ http://genome-www5.stanford.edu/  http://www.yeastgenome.org/ http://www.yeastgenome.org/  http://web.wi.mit.edu/young/cellcycle/ http://web.wi.mit.edu/young/cellcycle/  http://www.genome.jp/kegg/ http://www.genome.jp/kegg/

9. Yeast Cell Cycle Control Time course data is combined with Richard Young’s cell cycle data to have 792 cell cycle genes. Gene expression data was normalized so that the average log2(ratio) over the course of the experiment is equal to 0 and further divided by standard deviation.

10. Yeast Cell Cycle Control Gene expression

11. Yeast Cell Cycle Control Gene expression data testing –Method: Fourier Transform Im= ∑sin(ωtj)x(tj) (1) Re = ∑cos(ωtj)x(tj) (2) I = A 2 + B 2 (3) Φ= tan -1 (Im/Re) (4) where ω=2*π/T

12. Yeast Cell Cycle Control

13. Result of data testing –Similar periodical property Sorting –Fourier Transform magnitudes –Phase (time of peak expression)

14. Yeast Cell Cycle Control

16. g1m/g1 s g2/m

17. Yeast Cell Cycle Control OrfPhaseOrfPhaseOrfPhase YPL187W''m/g1''YJL078C''g1''YBR009C''s' 'YJL159W''m/g1''YJL115W''g1''YDR224C''s' 'YKL185W''m/g1''YPL267W''g1''YBR010W''s' 'YKL164C''m/g1''YBL035C''g1''YBL003C''s' 'YKL163W''m/g1''YLR286C''g1''YMR003W''s/g2' 'YDR261C''s''YDR097C''g1''YML052W''g2/m' 'YOR307C''g1''YGR189C''g1''YHL028W''g2/m' 'YLR079W''m/g1''YIL066C''g1''YPR149W''g2/m' 'YKR077W''g1''YBR088C''g1''YMR032W''g2/m' 'YBR158W''m/g1''YDL003W''g1''YLR190W''g2/m' 'YOR308C''g1''YHR143W''g1''YBR038W''g2/m' 'YNL327W''m/g1''YAR007C''g1''YBR092C''g2/m' 'YBR108W''g1''YBR089W''g1''YDR033W''g2/m' 'YLR049C''g1''YOL090W''g1''YDR225W''s' 'YGL028C''g1''YPL256C''g1''YBR054W''g2/m' 'YGR044C''g1''YOL007C''g1''YNL160W''m/g1' 'YCL024W''g1''YNL030W''s'

18. Yeast Cell Cycle Control

19. Genes are regulated in a periodic manner coincident with the cell cycle. Such regulation is required for proper functioning of the control mechanism to maintain events’ order during cell cycle.

20. Yeast Cell Cycle Model How do physicists study regulatory process of cell cycle? –To implement the yeast cell cycle with the most simplified network.

21. Yeast Cell Cycle Model  The network was simplified with the components having just on-off characteristics.  Thus, in the model each node only has two states, Si=1(active state) and Si=0(inactive state), with total 11 nodes. 1 0

22. Yeast Cell Cycle Model  The protein states propagation rule:

23. Yeast Cell Cycle Model  Fixed Points

24. Yeast Cell Cycle Model  Biological Pathway Temporal evolution of protein states for the cell-cycle network

26. Yeast Cell Cycle Model Conclusion: ---- High stability and robustness ---- More stable with more components involved

27. Transcriptional Regulatory Network Cell cycle regulation program is mainly due to gene expression. Gene activation and repression is via the transcription of sequence-specific DNA-binding transcription factors.

28. Transcriptional Regulatory Network The yeast cell cycle gene expression program is regulated by nine known cell cycle transcriptional factors. These cell cycle transcription factors each regulates a group of genes, function during one stage of the cell cycle

29. Transcriptional Regulatory Network

30. Genomic analysis of regulatory network dynamics reveals large topological changes(Nature,2004) NICHOLAS M. LUSCOMBE, M. MADAN BABU, HAIYUAN YU, MICHAEL SNYDER, SARAH A. TEICHMANN & MARK GERSTEIN http://sandy.topnet.gersteinlab.org/ –409 out of 792 cell cycle genes involved in 3459 genes that constitute the yeast genome network.

31. Transcriptional Regulatory Network G1/S: Mbp1(YDL056W) Swi4(YER111C) Swi6(YLR182W)

32. Transcriptional Regulatory Network G2/M: Fkh2(YNL068C) Ndd1(YOR372C) Mcm1(YMR043W)

33. Transcriptional Regulatory Network M/G1: Mcm1(YMR043W) Swi5(YDR146C) Ace2(YLR131C)

34. Transcriptional Regulatory Network

35. G1/S: Mbp1(YDL056W) Swi6(YLR182W) Swi4(YER111C)

36. Transcriptional Regulatory Network Single transcription factor –Fraenkel Lab - Yeast regulatory map

37. Transcriptional Regulatory Network G1/S: Mbp1(YDL056W) Swi6(YLR182W) Swi4(YER111C)

38. Transcriptional Regulatory Network Three transcription factors (AND logic) –Fraenkel Lab - Yeast regulatory map

39. Transcriptional Regulatory Network G1/S: Mbp1(YDL056W) Swi6(YLR182W) Swi4(YER111C)

40. Transcriptional Regulatory Network Two transcription factors (OR logic) –Fraenkel Lab - Yeast regulatory map

41. Further Work Combining expression data and binding data to find gene regulatory network Find logic control between TF and genes, especially combinatorial control (AND,OR,NOR,NAND,XOR) Build a dynamic model.

42. Acknowledgement Supervisor –Dr. Lei-han Tang Team member –Hui Sheng –Liang Shenghua –Wang Chao