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

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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.

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

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Lucy Ham

University of Melbourne, Melbourne, Australia

For correspondence
lucy.ham@unimelb.edu.au

Competing interests
The authors declare that no competing interests exist.
Marcel Jackson

La Trobe University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Michael Stumpf

University of Melbourne, Melbourne, Australia

For correspondence
mstumpf@unimelb.edu.au

Competing interests
The authors declare that no competing interests exist.

"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.

Copyright

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.