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

Abstract

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.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Peter L Freddolino

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5821-4226
  2. Jamie Yang

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Amir Momen-Roknabadi

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Saeed Tavazoie

    Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    st2744@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2183-4162

Funding

NIH Office of the Director (8DP1ES022578)

  • Saeed Tavazoie

National Institutes of Health (K99 (GM097033-01A1))

  • Peter L Freddolino

National Institutes of Health (MSTP)

  • Jamie Yang

National Institutes of Health (R01-AI077562)

  • Saeed Tavazoie

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2018, Freddolino et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,177
    views
  • 708
    downloads
  • 28
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Peter L Freddolino
  2. Jamie Yang
  3. Amir Momen-Roknabadi
  4. Saeed Tavazoie
(2018)
Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry
eLife 7:e31867.
https://doi.org/10.7554/eLife.31867

Share this article

https://doi.org/10.7554/eLife.31867

Further reading

    1. Biochemistry and Chemical Biology
    2. Computational and Systems Biology
    A Sofia F Oliveira, Fiona L Kearns ... Adrian J Mulholland
    Short Report

    The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits.

    1. Computational and Systems Biology
    George N Bendzunas, Dominic P Byrne ... Natarajan Kannan
    Research Article

    In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications, including phosphorylation of Ser/Thr residues and oxidation of cysteine (Cys) residues. While regulation by activation segment phosphorylation of Ser/Thr residues is well understood, relatively little is known about how oxidation of cysteine residues modulate catalysis. In this study, we investigate redox regulation of the AMPK-related brain-selective kinases (BRSK) 1 and 2, and detail how broad catalytic activity is directly regulated through reversible oxidation and reduction of evolutionarily conserved Cys residues within the catalytic domain. We show that redox-dependent control of BRSKs is a dynamic and multilayered process involving oxidative modifications of several Cys residues, including the formation of intramolecular disulfide bonds involving a pair of Cys residues near the catalytic HRD motif and a highly conserved T-loop Cys with a BRSK-specific Cys within an unusual CPE motif at the end of the activation segment. Consistently, mutation of the CPE-Cys increases catalytic activity in vitro and drives phosphorylation of the BRSK substrate Tau in cells. Molecular modeling and molecular dynamics simulations indicate that oxidation of the CPE-Cys destabilizes a conserved salt bridge network critical for allosteric activation. The occurrence of spatially proximal Cys amino acids in diverse Ser/Thr protein kinase families suggests that disulfide-mediated control of catalytic activity may be a prevalent mechanism for regulation within the broader AMPK family.