Network Dynamics of Budding Yeast Cell Cycle

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. MPF synthesis degradation degradation synthesis SPF 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.

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://www.yeastgenome.org/ • http://web.wi.mit.edu/young/cellcycle/ • 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 = A2 + B2 (3) Φ= tan-1(Im/Re) (4) where ω=2*π/T

12. Yeast Cell Cycle Control

13. Yeast Cell Cycle Control • Result of data testing • Similar periodical property • Sorting • Fourier Transform magnitudes • Phase (time of peak expression)

14. Yeast Cell Cycle Control

15. Yeast Cell Cycle Control

16. g1 m/g1 s g2/m Yeast Cell Cycle Control

17. Yeast Cell Cycle Control

18. Yeast Cell Cycle Control

19. Yeast Cell Cycle Control • 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. Transcriptional Regulatory Network • 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. Transcriptional Regulatory Network • 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