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Network Dynamics of
Budding Yeast Cell Cycle
Supervisor: Dr. Lei-han Tang
Presented by Cai Chunhui
April 16, 2005
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Presentation Outline
Introduction to budding yeast cell cycle
Budding Yeast Cell Cycle Control
Tang Chao’s model
Transcriptional regulation network
Further work
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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.
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Yeast Cell Cycle Control
• Yeast Cell Cycle is tightly regulated by cell cycle control systemA 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.
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Yeast Cell Cycle Control
• Yeast Cell-cycle Control System is based on
The activity of the cyclin-dependent kinase (CDK) Cdc28.
Gene regulation.
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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
synthesisdegradation
SPF
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Yeast Cell Cycle Control
• Gene Regulation is poorly understand
-- ~800 out of 6126 genes oscillate during cell cycle, with unknown functions of most genes
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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/
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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.
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Yeast Cell Cycle Control
• Gene expression
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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
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Yeast Cell Cycle Control
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Yeast Cell Cycle Control
• Result of data testing– Similar periodical property
• Sorting– Fourier Transform magnitudes– Phase (time of peak expression)
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Yeast Cell Cycle Control
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Yeast Cell Cycle Control
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Yeast Cell Cycle Control
g1 m/g1
s
g2/m
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Yeast Cell Cycle ControlOrf Phase Orf Phase Orf Phase
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'
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Yeast Cell Cycle Control
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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.
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Yeast Cell Cycle Model
• How do physicists study regulatory process of cell cycle?– To implement the yeast cell
cycle with the most simplified network.
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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
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Yeast Cell Cycle Model
The protein states propagation rule:
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Yeast Cell Cycle Model
Fixed Points
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Yeast Cell Cycle Model
Biological PathwayTemporal evolution of protein states for the cell-cycle network
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Yeast Cell Cycle Model
• Conclusion:
---- High stability and robustness
---- More stable with more components involved
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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.
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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
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Transcriptional Regulatory Network
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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.
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Transcriptional Regulatory Network
• G1/S:
Mbp1(YDL056W)
Swi4(YER111C)
Swi6(YLR182W)
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Transcriptional Regulatory Network
• G2/M:
Fkh2(YNL068C)
Ndd1(YOR372C)
Mcm1(YMR043W)
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Transcriptional Regulatory Network
• M/G1:
Mcm1(YMR043W)
Swi5(YDR146C)
Ace2(YLR131C)
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Transcriptional Regulatory Network
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Transcriptional Regulatory Network
• G1/S:
Mbp1(YDL056W)
Swi6(YLR182W)
Swi4(YER111C)
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Transcriptional Regulatory Network
• Single transcription factor– Fraenkel Lab - Yeast regulatory map
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Transcriptional Regulatory Network
• G1/S:
Mbp1(YDL056W)
Swi6(YLR182W)
Swi4(YER111C)
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Transcriptional Regulatory Network
• Three transcription factors (AND logic)– Fraenkel Lab - Yeast regulatory map
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Transcriptional Regulatory Network
• G1/S:
Mbp1(YDL056W)
Swi6(YLR182W)
Swi4(YER111C)
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Transcriptional Regulatory Network
• Two transcription factors (OR logic)– Fraenkel Lab - Yeast regulatory map
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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.
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Acknowledgement
• Supervisor– Dr. Lei-han Tang
• Team member– Hui Sheng– Liang Shenghua– Wang Chao