1. 2IF35: Formal Modelling in Cell Biology
Lambda switch in GINsim
Fall 2007
Mohammed El-Kebir
Koen Schuurmans
Monique Hendriks
Tim Muller

2. Outline Genetic toggle switch GINsim Bacteriophage Lambda phage
GINsim model
Comparison
Conclusion
Monique t/m GINsim, Mohammed vanaf Bacteriophage

3. Genetic toggle switch Two genes: b and c
Promoters pb and pc
Resulting proteins: B and C
Transcription factors: A, B, C
A promotes expression of gene b and c
B inhibits expression of gene c
C inhibits expression of gene b
A, B en C heten transcriptiefactoren
Als A op ene promoter, dan blockt B de andere
Als A op andere promoter, dan blockt C de ene
Blijft na keuze vastzitten in 1 toestand, stabiel, alleen door invloed van buitenaf weer switchen

4. GINsim GINsim is made for modeling genetic regulatory networks
Building blocks are genes, genes have
Basal expression level
Maximal expression level
Genes can be connected with each other, for
Activation
Inhibition
Abstractie naar genetisch niveau, dus alleen interactie tussen genen (die expressieniveau beinvloeden)
Basal = zonder binding van transcriptiefactoren

5. GINsim (ctn.) Genetic switch model:
State space generation (a = 1, b = 0, c = 0):
GINsim gebaseerd op petrinet-aanpak
Transcriptie van a leidt tot A (transcriptiefactor).
Qualtitatief

6. GINsim (ctn.) Internally GINsim is based on petri-nets.
It is possible to export the regulatory network as a petrinet (PNML)
Unfortunately, exported PNMLs are incorrect
Every gene corresponds with a place
#Tokens in a place denote the expression level
Transitions are the various modi of the gene (inhibited, activated, basal, etc.)
Gene products: eiwitten

7. Bacteriophage Virus that only infects bacteria A phage consists of:
Etymology: eater of bacteria
A phage consists of:
Head with DNA or RNA
Tail for attachment to cell membrane and penetration

8. Bacteriophage (ctn.) A bacteriophage may have a
Lytic cycle Virus keeps on reproducing, ultimately causing lysis of host cell
Lysogenic cycle DNA of phage is merged with DNA of host. Peaceful coexistence with the host.

9. Lambda phage Lambda phage is a bacteriophage
Infects the E. coli bacterium
Has both a lytic and a lysogenic cycle
The choice of the cycle depends on the environment:
If the environment is not supporting the growth of more potential hosts, then there is no reason to reproduce
If the environment is right for potential hosts, then reproduction will result in more infected cells.
The choice is regulated by the lambda switch
Extremely stable (transition to lytic growth once every 5000 years)
But upon environmental change: lytic growth

10. Lambda phage (cnt.) Lysogenic cycle CII CI2 CII CI CI CIII
CII binds to promoter Pre
Gene cI is expressed
CI binds to PI
Gene cIII is expressed
Stabilization
CIII prevents destruction of CII
Dimerized CI binds to Or1 and Or2 prevents expression of cro and enhances expression of cI CI
Pijltjes zijn excitatory en vierkantjes zijn inhibitory.
CIII

11. Lambda phage (cnt.) Lytic cycle CII Cro Cro Cro2
CII degraded by protease before reaching Pre
In absence of CII Pr is weakly active
Gene cro is expressed
Stabilization
Dimer Cro2 binds to Or2 and Or1
prevents expression of cI and enhances expression of cro
Pijltjes zijn excitatory en vierkantjes zijn inhibitory.

12. Lambda phage (cnt.) Lambda switch [CII]  A
As soon as cI or cro is expressed, the switched is locked (just like with the expression of b or c)
CII
Pijltjes zijn excitatory en vierkantjes zijn inhibitory.

13. Comparison Maude PRISM GINsim Qualitative Yes Quantitative No
Model checking
LTL
TPCTL
Path finding
Limitations
Purely qualitative
State explosion for realistic models
Only regulatory genetic networks