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Cell Syst. 2018 Oct 24;7(4):384-397.e6. doi: 10.1016/j.cels.2018.08.002. Epub 2018 Sep 19.

Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability.

Author information

1
Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA.
2
Center for Nanophase Materials Science, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA.
3
Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: leor.weinberger@gladstone.ucsf.edu.

Abstract

Transcription is an episodic process characterized by probabilistic bursts, but how the transcriptional noise from these bursts is modulated by cellular physiology remains unclear. Using simulations and single-molecule RNA counting, we examined how cellular processes influence cell-to-cell variability (noise). The results show that RNA noise is higher in the cytoplasm than the nucleus in ∼85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states. This multi-state translation-degradation of mRNA also causes substantial noise amplification in protein levels, ultimately accounting for ∼74% of intrinsic protein variability in cell populations. Overall, the results demonstrate how noise from transcriptional bursts is intrinsically amplified by mRNA processing, leading to a large super-Poissonian variability in protein levels.

KEYWORDS:

bursting; mRNA degradation; mathematical modeling; noise amplification; noise attenuation; nuclear export; single molecule RNA FISH; stochastic noise; transcription; translation

PMID:
30243562
PMCID:
PMC6202163
DOI:
10.1016/j.cels.2018.08.002
[Indexed for MEDLINE]
Free PMC Article

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