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

Signal Processing in Single Cells

Tony

03/30/2005

How signals are transmitted through gene cascades in noisy cellular environments?

The Question

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

Gene cascade

Experimental tricks

• Regulator dilution method

• Relative fluorescence intensity of individual protein molecules apparent number of molecules per cell.

• Hill function

Mean shape

Fluctuations• After normalizing production rates to the average cell-cyc

le 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 indi

vidual 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 meta

bolites, ribosomes, and polymerases.– Contributes a variation in protein production rates of ~35%.

Time scales of the fluctuations

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.

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.

Gene cascade

Experimental results

Model

Model

• 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 (log

arithmic 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

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.