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Enhancement of cellular memory by reducing stochastic transitions

Author

Listed:
  • Murat Acar

    (Massachusetts Institute of Technology)

  • Attila Becskei

    (Massachusetts Institute of Technology)

  • Alexander van Oudenaarden

    (Massachusetts Institute of Technology)

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.

Suggested Citation

  • Murat Acar & Attila Becskei & Alexander van Oudenaarden, 2005. "Enhancement of cellular memory by reducing stochastic transitions," Nature, Nature, vol. 435(7039), pages 228-232, May.
    • Handle: RePEc:nat:nature:v:435:y:2005:i:7039:d:10.1038_nature03524
    DOI: 10.1038/nature03524
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    Cited by:

    1. Liberman, Uri & Behar, Hilla & Feldman, Marcus W., 2016. "Evolution of reduced mutation under frequency-dependent selection," Theoretical Population Biology, Elsevier, vol. 112(C), pages 52-59.
    2. Tobias May & Lee Eccleston & Sabrina Herrmann & Hansjörg Hauser & Jorge Goncalves & Dagmar Wirth, 2008. "Bimodal and Hysteretic Expression in Mammalian Cells from a Synthetic Gene Circuit," PLOS ONE, Public Library of Science, vol. 3(6), pages 1-7, June.
    3. M. Kleshnina & K. Kaveh & K. Chatterjee, 2020. "The role of behavioural plasticity in finite vs infinite populations," Papers 2009.13160, arXiv.org.
    4. Arjun Raj & Charles S Peskin & Daniel Tranchina & Diana Y Vargas & Sanjay Tyagi, 2006. "Stochastic mRNA Synthesis in Mammalian Cells," PLOS Biology, Public Library of Science, vol. 4(10), pages 1-13, September.
    5. Zhou, Peipei & Cai, Shuiming & Liu, Zengrong & Chen, Luonan & Wang, Ruiqi, 2013. "Coupling switches and oscillators as a means to shape cellular signals in biomolecular systems," Chaos, Solitons & Fractals, Elsevier, vol. 50(C), pages 115-126.
    6. Carl Song & Hilary Phenix & Vida Abedi & Matthew Scott & Brian P Ingalls & Mads Kærn & Theodore J Perkins, 2010. "Estimating the Stochastic Bifurcation Structure of Cellular Networks," PLOS Computational Biology, Public Library of Science, vol. 6(3), pages 1-11, March.
    7. Matthieu Wyart & David Botstein & Ned S Wingreen, 2010. "Evaluating Gene Expression Dynamics Using Pairwise RNA FISH Data," PLOS Computational Biology, Public Library of Science, vol. 6(11), pages 1-14, November.
    8. Najme Khorasani & Mehdi Sadeghi & Abbas Nowzari-Dalini, 2020. "A computational model of stem cell molecular mechanism to maintain tissue homeostasis," PLOS ONE, Public Library of Science, vol. 15(7), pages 1-25, July.
    9. Bingnan Li & Patrice Zeis & Yujie Zhang & Alisa Alekseenko & Eliska Fürst & Yerma Pareja Sanchez & Gen Lin & Manu M. Tekkedil & Ilaria Piazza & Lars M. Steinmetz & Vicent Pelechano, 2023. "Differential regulation of mRNA stability modulates transcriptional memory and facilitates environmental adaptation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Benjamin B Kaufmann & Qiong Yang & Jerome T Mettetal & Alexander van Oudenaarden, 2007. "Heritable Stochastic Switching Revealed by Single-Cell Genealogy," PLOS Biology, Public Library of Science, vol. 5(9), pages 1-8, September.

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