1. Signal Processing in Single Cells Tony 03/30/2005

2. How signals are transmitted through gene cascades in noisy cellular environments? The Question

3. Work by Rosenfeld et al Gene Regulation Function (GRF) –The relation between the concentration of active transcription factors in a cell and the rate at which their downstream gene products are produced through transcription and translation. Three fundamental aspects of GRF to study: –Mean shape –Typical deviation from this mean –Time scale over which such fluctuations persist

4. Gene cascade

5. Experimental tricks Regulator dilution method Relative fluorescence intensity of individual protein molecules  apparent number of molecules per cell. Hill function

6. Mean shape

7. Fluctuations After normalizing production rates to the average cell- cycle phase, substantial variation still remains in the production rates, and their standard deviation is ~40% of the mean GRF. Intrinsic noise –Results from stochasticity in the biochemical reactions at an individual gene and would cause identical copies of the same gene to express at different levels. –~20% of the total noise Extrinsic noise –Originates from fluctuations in cellular components such as metabolites, ribosomes, and polymerases. –Contributes a variation in protein production rates of ~35%.

8. Time scales of the fluctuations

9. Conclusions Slow fluctuations give the genetic circuits memory, or individuality, lasting roughly one cell cycle. They present difficulty for modeling genetic circuits. There is thus a fundamental tradeoff between accuracy and speed in purely transcriptional responses. Accurate cellular responses on faster time scales are likely to require feedback from their output.

10. Work by Pedraza & Oudenaarden Expression correlations between genes in single cells were measured. A model was developed that explains the complex behavior exhibited by the correlations and reveals the dominant noise sources.

11. Gene cascade

12. Experimental results

13. Model

14. Langevin approach Noise terms: –Intrinsic noise at specific gene –Transmitted intrinsic noise from the upstream genes The Intrinsic noise for upstream gene The effect of temporal averaging The susceptibility of downstream gene to upstream gene (logarithmic gain) –Global noise modulated by the network The direct effect on the gene The transmitted effect from upstream genes The effect of the correlated transmission

15. Results Even in a network where all components have low intrinsic noise, fluctuations can be substantial and the distributions of expression levels depend on the interactions between genes.