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2IF35: Formal Modelling in Cell Biology

2IF35: Formal Modelling in Cell Biology. Lambda switch in GINsim Fall 2007 Mohammed El-Kebir Koen Schuurmans Monique Hendriks Tim Muller. Outline. Genetic toggle switch GINsim Bacteriophage Lambda phage GINsim model Comparison Conclusion. Genetic toggle switch. Two genes: b and c

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2IF35: Formal Modelling in Cell Biology

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  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

  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

  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

  5. GINsim (ctn.) • Genetic switch model: • State space generation (a = 1, b = 0, c = 0):

  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.)

  7. Bacteriophage • Virus that only infects bacteria • 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 cycleVirus keeps on reproducing, ultimately causing lysis of host cell • Lysogenic cycleDNA 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. CII CI CI CI2 CII CIII Lambda phage (cnt.) • Lysogenic cycle • 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 Or2prevents expression of cro and enhances expression of cI

  11. CII Cro Cro Cro2 Lambda phage (cnt.) • Lytic cycle • 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

  12. CII 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)

  13. Comparison

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