Stochastic Models of Cell Cycle Regulation in Eukaryotes

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Stochastic Models of Cell Cycle Regulation in
Eukaryotes
John J. Tyson Virginia Polytechnic
Institute Virginia Bioinformatics Institute

• John J. Tyson
• Virginia Polytechnic Institute
• Virginia Bioinformatics Institute

DARPA, NIH, McDonnell Foundation
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G1
cell division
The cell cycle is the sequence of events
whereby a growing cell replicates all its
components and divides them more-or-less
evenly between two daughter cells ...
S
DNA replication
M mitosis
G2
3
G1
cell division
S
Cyclin-dependent kinase Cyclin B
DNA replication
Cdk1
CycB
M mitosis
G2
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First things firstDeterministic models of cell
cycle regulation
Kathy Chen
Attila Csikasz-Nagy
Bela Novak
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Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
E2FA
Csikasz-Nagy et al. Biophys J (2006)
CycB
CycA
E2FI
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The mathematical model
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37,500
http//mpf.biol.vt.edu Go to Budding Yeast Model
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Why bother with a stochastic model?
Fission Yeast
Cells are small and progression through the cell
cycle is very noisy
age_at_ division
size_at_ division
80
60
of cells
40
20
12 15 90 120 150 Length
Time (mm) (min) CV 7.5
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Cells are not very fussy about how long it takes
to do DNA synthesis and mitosis, nor
(consequently) about how large they are at
division. Size fluctuations can be corrected in
the next generation.
cdc2-33
WT
Fantes (1977)
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Cells are not very fussy about how long it takes
to do DNA synthesis and mitosis, nor
(consequently) about how large they are at
division. Size fluctuations can be corrected in
the next generation.
daughter
cdc2-33
Cell size at division is uncorrelated from mother
to daughter
WT
mother
Fantes (1977)
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Kar et al. Fig. 1a
Koch Schaechter (1962)
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Kar et al. Fig.1a
Koch Schaechter (1962)
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So, whats to explain?
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So, whats to explain?
(1) Small numbers of molecules
Table 1. Numbers of molecules (per haploid yeast
cell) for several cell cycle genes.
Swain, Paulsson, etc.
Protein data (a,b) from a Ghaemmaghami (2003),
b Cross (2002) mRNA data from
http//web.wi.mit.edu/young/expression/transcripto
me.html
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So, whats to explain?
(2) Mutants Fission Yeast wee1ts cdc25D
Trimodal distribution of cycle times
Novak, Sveiczer, Mitchison
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So, whats to explain?
(3) Single-cell measurements
The effects of molecular noise and size control
on variability in the budding yeast cell
cycle Stefano Di Talia, Jan M. Skotheim, James M.
Bean, Eric D. Siggia Frederick R. Cross Nature
448, 947-951(23 August 2007)
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Sources of noise

• Intrinsic molecular fluctuations in the
  control network
• Extrinsic inequities in the division process