Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry

  • Freddolino P
  • Yang J
  • Momen-Roknabadi A
  • et al.
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Cells adapt to familiar changes in their environment by activating predefined regulatory programs that establish adaptive gene expression states. These hard-wired pathways, however, may be inadequate for adaptation to environments never encountered before. Here, we reveal evidence for an alternative mode of gene regulation that enables adaptation to adverse conditions without relying on external sensory information or genetically predetermined cis-regulation. Instead, individual genes achieve optimal expression levels through a stochastic search for improved fitness. By focusing on improving the overall health of the cell, the proposed stochastic tuning mechanism discovers global gene expression states that are fundamentally new and yet optimized for novel environments. We provide experimental evidence for stochastic tuning in the adaptation of Saccharomyces cerevisiae to laboratory-engineered environments that are foreign to its native gene-regulatory network. Stochastic tuning operates locally at individual gene promoters, and its efficacy is modulated by perturbations to chromatin modification machinery.To survive, cells have to adapt to changes in their environment. Organisms can do so by constantly modifying the expression of their genes. For example, bacteria exposed to high temperatures turn on heat-shock genes to help them cope.Responses to familiar environmental changes take place thanks to specific, hard-wired molecular pathways. These transmit external signals to transcription factors, proteins that can bind DNA near a gene to regulate its expression. Yet, such established responses may not exist for stressful conditions that cells have never encountered during their evolutionary history. In this case, how can organisms adjust which genes to express, and at what levels?Here, Freddolino et al. theorize that, in a new environment, individual genes can randomly increase or decrease their level of expression. If a change ends up being good for the survival of the cell, it is further reinforced. This ‘stochastic tuning’ would allow organisms to find the optimal levels of gene expression without using genetically predetermined pathways that involve transcription factors.Mathematical simulations suggest that this mechanism can improve the growth and survival of a cell in a new environment. Diverse experiments demonstrate that a phenomenon consistent with stochastic tuning occurs in yeasts. The organisms are genetically modified so that their transcription factors can no longer activate URA3, a gene required to grow in conditions lacking a chemical called uracil. Yet, these altered yeast cells still manage to boost their URA3 expression in a uracil-free environment.Stochastic tuning could thus work alongside other types of conventional gene regulation to help cells adapt to new and challenging living conditions. For instance, this may be how cancerous cells survive and thrive when facing chemotherapy drugs.




Freddolino, P. L., Yang, J., Momen-Roknabadi, A., & Tavazoie, S. (2018). Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry. ELife, 7.

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