Pathway dynamics can delineate the sources of transcriptional noise in gene expression

  1. Lucy Ham  Is a corresponding author
  2. Marcel Jackson
  3. Michael Stumpf  Is a corresponding author
  1. University of Melbourne, Australia
  2. La Trobe University, Australia

Abstract

Single-cell expression profiling opens up new vistas on cellular processes. Extensive cell-to-cell variability at the transcriptomic and proteomic level has been one of the stand-out observations. Because most experimental analyses are destructive we only have access to snapshot data of cellular states. This loss of temporal information presents significant challenges for inferring dynamics, as well as causes of cell-to-cell variability. In particular, we typically cannot separate dynamic variability from within cells ('intrinsic noise') from variability across the population ('extrinsic noise'). Here we make this non-identifiability mathematically precise, allowing us to identify new experimental set-ups that can assist in resolving this non-identifiability. We show that multiple generic reporters from the same biochemical pathways (e.g. mRNA and protein) can infer magnitudes of intrinsic and extrinsic transcriptional noise, identifying sources of heterogeneity. Stochastic simulations support our theory, and demonstrate that 'pathway-reporters' compare favourably to the well-known, but often difficult to implement, dual-reporter method.

Data availability

All methods and simulation results are shared via a github site.There is no original data associated with this manuscript.

Article and author information

Author details

  1. Lucy Ham

    University of Melbourne, Melbourne, Australia
    For correspondence
    lucy.ham@unimelb.edu.au
    Competing interests
    The authors declare that no competing interests exist.
  2. Marcel Jackson

    La Trobe University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael Stumpf

    University of Melbourne, Melbourne, Australia
    For correspondence
    mstumpf@unimelb.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3577-1222

Funding

University of Melbourne (DRM)

  • Lucy Ham
  • Michael Stumpf

Volkswagen Foundation (93 062)

  • Michael Stumpf

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

Reviewing Editor

  1. Ramon Grima

Version history

  1. Preprint posted: September 30, 2020 (view preprint)
  2. Received: April 12, 2021
  3. Accepted: October 11, 2021
  4. Accepted Manuscript published: October 12, 2021 (version 1)
  5. Version of Record published: November 22, 2021 (version 2)

Copyright

© 2021, Ham 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.

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  1. Lucy Ham
  2. Marcel Jackson
  3. Michael Stumpf
(2021)
Pathway dynamics can delineate the sources of transcriptional noise in gene expression
eLife 10:e69324.
https://doi.org/10.7554/eLife.69324

Share this article

https://doi.org/10.7554/eLife.69324

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