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Uri Alon’s lab 10/02

Uri Alon’s lab 10/02. Network of transcriptional interactions in E. coli. Thieffry, Collado-Vides, 1998 Shen-Orr, Alon, Nature Genetics 2002. (Rosenfeld,Elowitz,Alon, JMB 323:785 2002). The assumptions. X is always expressed X requires S x to be active X* Y requires S y to be active Y*

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Uri Alon’s lab 10/02

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  1. Uri Alon’s lab 10/02

  2. Networkof transcriptional interactions in E. coli Thieffry, Collado-Vides, 1998 Shen-Orr, Alon, Nature Genetics 2002

  3. (Rosenfeld,Elowitz,Alon, JMB 323:785 2002)

  4. The assumptions • X is always expressed • X requires Sx to be active X* • Y requires Sy to be active Y* • Functional FFL - a change in Sx causes a change in Y sufficient to cause a change in Z

  5. Mangan et. al, PNAS (2003)

  6. Logical gate • AND gate • f(X*,Kxz) * f(Y*,Kyz) • where X and Y are either activators or repressors • OR gate • Sum of X and Y regulation functions taking competitive binding into account • question – why not allow for competitive binding in AND gate

  7. Steady state :Coherent Type 1 – AND gate Sx X Z production requires Sx AND Sy Sy Y Z

  8. Steady state :Coherent Type 2 – AND gate Sx X Z production requires Not Sx AND Sy Sy Y Z

  9. Steady state :Coherent Type 3 – AND gate Sx Z production requires (Not Sx +Sy) OR (Not Sx + Not Sy) in other words Not Sx X Sy Y Z Sy does not matter because Y is not expressed

  10. Steady state :Coherent Type 4 – AND gate Sx X Z production requires Sx Sy Y Z Sy does not matter because Y is repressed

  11. Steady state: Summary of coherent AND gate FFL • Type 1 Sx AND Sy • Type 2 Not Sx AND Sy • Type 3 Not Sx • Type 4 Sx • Type 1 & 2 appear abundantly in coli and yeast unlike type 3 & 4

  12. Steady state: Quick Summary of incoherent AND gate FFL • Type 1 Sx AND Not Sy • Type 2 Not Sx AND Not Sy • Type 3 0 • Type 4 0 • Again, only 1 & 2 use both Sx and Sy and in yeast they are the only ones to appear abundantly (in coli incoherent FFL are rare)

  13. Kinetics: Coherent FFL are sign sensitive delay elements Sx Sign sensitive – Get response (i.e. delay) in one direction (i.e. on to off) but not in the other (off to on) X Sy Y Z Sign sensitivity direction depends on Z’s steady state activation functions – when Sx is required for activation delay is in on step and when NOT Sx delay is in off step

  14. FFL function – a filter • Persistence detector • A sign-sensitive delay • Database -> Motifs -> Theory -> Experiments Threshold for Y being active Mangan et. al, PNAS (2003)

  15. Maximalresponse to a pulse is filtered by FFL Input pulse to X of duration T T Response X Z X Y Z Simulation Pulse duration T

  16. Glucose pulse experiment shows filtering by arabinose FFL Max response crp lacZ crp Delay per cascade step ~ one cell cycle araC araB Pulse duration [min] Mangan, et. al. JMB (2003).

  17. Kinetics: Incoherent FFL can generate pulses controlled by Sy Sx Sx X X Sy Sy Y Y Not at steady state Z Z This is our AND gate

  18. Kinetics: Incoherent FFL can accelerate response Sx Sx make promoter stronger X Sy Sy X Y Y Z Z

  19. OR gates – generally reversed Sx X Sy Y Z

  20. comparing networks of different sizes for similarity in local structure Normalized significance Different Subgraphs

  21. Uri Alon’s lab 10/02

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