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Stochastische Genexpression Literatur Kaern et al. Nature Reviews Genetics Vol.6 p.451 (2005) Ozbudak, Oudenaarden et al (2004) Multistability in the lactose.

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Presentation on theme: "Stochastische Genexpression Literatur Kaern et al. Nature Reviews Genetics Vol.6 p.451 (2005) Ozbudak, Oudenaarden et al (2004) Multistability in the lactose."— Presentation transcript:

1 Stochastische Genexpression Literatur Kaern et al. Nature Reviews Genetics Vol.6 p.451 (2005) Ozbudak, Oudenaarden et al (2004) Multistability in the lactose utilization network of Escherichia coli, Nature 427, p737 Vorlesung System-Biophysik 18. Dez Genetische Schalter und Multistabilität

2 Das Operon-Modell Francois Jacob und Jaques Monod, 1961 operon Operon: Genetische Funktionseinheit, die aus regulierten Genen mit verwandter Funktion besteht und enthält: - Promotor: Bindungsstelle für RNA-Polymerase - Operator: kontrolliert Zugang der RNA-Polymerase zu Strukturgen - Strukturgene: Polypeptide codierende Gene zusätzlich: Regulatorgen: codiert Repressor Campbell, N.A., Biology

3 A Transkription-Aktivator and a Transkription-Repressor control the lac-Operon

4 Genregulation and boolean networks from Weiss, 2000

5 Boolean expression of the Lac-Operon

6 Genetische Netze transcription translation Genregulatorisches Protein

7 Transkription factors show cooperativity (e.g. by dimer-formation) Cooperative binding

8 Wiederholung

9 Genregulation and boolean Network from Weiss, 2000

10 (Nature, Dec 99)

11 the genetic Toggle Switch (Flip-Flop)


13 Weiss et al.

14 the repressilator (genetic oscillator)

15 Genetically controlled oscillation of about 24 hours, adapted to the day-night rythm. Der 24h Rythm is robust, the phase is coupled to the light/dark cycle. A single gen-mutation is responsible for the familial advanced sleep phase syndrome, FASPS. [Latein. circa about + dies a day] Circadian Rhythm – the biological clock

16 Die circadiane Uhr at Drosophila The complex fromation Per/Tim supports the entry in the nucleus and stays stable there for 8-10h. This slows down the feedback loop. Two proteins Per (Period) and Tim (timeless) regulate each other and form a dimere complex. Monomeres of Per in the nucleus supresses expression. The kinase DBT (double time) phosphorylates und degrades Per.

17 Decelerated negative feedback via dclk (dclock) (degradation) and dbt (doubletime) (Transport) Synchronization (Entrainment) due to sunlight dependent TIM degradation rate

18 A couple of phosporilation steps are part of deceleration mechanism

19 What is life ? 1. How can biological order (life) be explaind by the basic laws of physics? 2. How does life deal with the statistic nature of molecular interactions?... wenn wir so empfindliche Organismen wären, daß ein einzelnes Atom oder meinet- wegen ein paar Atome einen wahrnehmbaren Eindruck auf unsere Sinnesorgane machen könnten - du lieber Himmel, wie sähe das Leben dann aus! Schrödinger considered 1943 the consequences of the molecular nature of the genetic code in a lecture about Physics and biology

20 The importance of statistical fluctuations in biology In a fluctuating environment, heterogeneous cell populations have better chances to grow. (e.g. control of lac.operon, immune system, lysis-networks of lambda-phage) Diversification in isogene phenotypes und celltypes (e.g. stem cell diversification) Efficiency increase in signal transduction (e.g. chemotaxis regulation oder stochastic resonance (ears)) Noise can be increased with positive feedback loops with advandtages: Stabilisation of metabolics / homeostasis Noise can be decreased via negative feedback loops

21 Biochemical noise: fluctuation of protein concentration Small numbers of copies of many components e.g. Polymerases, regolatory proteins, Stochastic effects in gene expression play an important role for variations of protein concentrations of bacteria wit identical genes Asymetries emerge, which are amplified by feedback loops and influence the development of the cell. Noise in the expression:

22 Deterministic model of gene expression from JJ Collins, Nature Reviews 2005

23 Definitions for noise noise Distribution Noise amplitude decreases with increasing number of particles! z: number of data points Rao, Wolf,Arkin, Nature 2002 Variance

24 finite size effect (noise) : mean value : standard deviation 0.1µM corresponds to 30 molecules/bacterium Decrease of the transcription rate and cell volume with equal factors keeps the protein level constant, but increases noise

25 beschreibt den Effekt, dass ein Heraufsetzen der translationsrate auch die Fluktuationen verstärkt. Herabsetzen von Transkriptionsrate und Zellvolumen Proteinlevel konstant Fluktuationen erhöht Translational bursting

26 Slow promotors increase noise Transcriptional bursting low promotor rate High transcription rate

27 Noise models Set of differntial equations (deterministic): Set of differential-equations (stochastic) Langevin equations: C: concentrations, t: time, v: stoichiometric matrix, r: rates, x(t): white noise Probability density function example isomerisation with k 1 = k 2 = 1s -1 k1k1 k2k2 Simulation for isomerisation : state A state B

28 Experiment: stochastisc Gen-Expression Distinguish between intrinsic noise (e.g. gene expression) and extrinsic noise(e.g. other cell components as RNA polymerase) Idea for an exeriment: Gene for CFP (green fluorescent Protein) und YFP (rot fluorecent Protein) are controlled by the same promotor, hence the mean concentration of CFP and YFP is equal => Expression probability should differ only due to intrinsic noise A: no intrinsic noise => noise is correlated red+green=yellow B: intrinsic noise => noise not correlated, different colors Elowitz, M. et al, Science 2002

29 Two distinguishable genes (CFP and YFP) controlled by the same promotor Low induction: (low fluorescence) high noise High induction : (high fluorescene) Low noise Elowitz, M. et al, Science 2002 Stochastische Genexpression in einer einzelnen Zelle

30 (noise) Intrinsic noise: inherent stochasticity at identical external conditions Extrinsic noise: cell to cell variance of expression Stochastic gene expression

31 Elowitz et al. 2002

32 hte intrinsisc noise decreases with increasing protein concentration Elowitz, M. et al, Science 2002

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