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Enhancement of cellular memory by reducing stochastic transitions

Nature volume 435, pages 228–232 (2005)Cite this article

Abstract

On induction of cell differentiation, distinct cell phenotypes are encoded by complex genetic networks1,2,3. These networks can prevent the reversion of established phenotypes even in the presence of significant fluctuations. Here we explore the key parameters that determine the stability of cellular memory by using the yeast galactose-signalling network as a model system. This network contains multiple nested feedback loops. Of the two positive feedback loops, only the loop mediated by the cytoplasmic signal transducer Gal3p is able to generate two stable expression states with a persistent memory of previous galactose consumption states. The parallel loop mediated by the galactose transporter Gal2p only increases the expression difference between the two states. A negative feedback through the inhibitor Gal80p reduces the strength of the core positive feedback. Despite this, a constitutive increase in the Gal80p concentration tunes the system from having destabilized memory to having persistent memory. A model reveals that fluctuations are trapped more efficiently at higher Gal80p concentrations. Indeed, the rate at which single cells randomly switch back and forth between expression states was reduced. These observations provide a quantitative understanding of the stability and reversibility of cellular differentiation states.

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Figure 1: The galactose signalling pathway.
Figure 2: History-dependent experiments reveal the regulatory interaction necessary for persistent memory.
Figure 3: Stability analysis of the GAL network.
Figure 4: Stochastic switching dynamics between two stable expression states (strain MA0188).

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Acknowledgements

We thank M. Thattai for stimulating discussions and helpful suggestions on measuring the escape rates; J. Pedraza, M. Kardar, O. Ozcan and S. Cabi for useful discussions; B. Kaufmann for help with image analysis; and B. Pando for comments on the manuscript. M.A. acknowledges support by an MIT Presidential Fellowship endowed by Praecis Pharmaceuticals, Inc. A.B. is a Long Term Fellow of the Human Frontiers Science Program. This work was supported by a NSF-CAREER and a NIH grant.

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  1. Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Murat Acar, Attila Becskei & Alexander van Oudenaarden

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  1. Murat Acar
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  3. Alexander van Oudenaarden
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Correspondence to Alexander van Oudenaarden.

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Supplementary Notes

This file contains information on the following: modelling the galactose signalling pathway; determining experimental escape rates; and the doxycycline inducible PTET system. It also contains additional references, Supplementary Figures S1-S7, Supplementary Table 1 (yeast strains used in this study) and Supplementary Table 2 (galactose depletion experiments). (PDF 889 kb)

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Acar, M., Becskei, A. & van Oudenaarden, A. Enhancement of cellular memory by reducing stochastic transitions. Nature 435, 228–232 (2005). https://doi.org/10.1038/nature03524

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