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Title: Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability

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 also 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.

Authors:
 [1];  [1]; ORCiD logo [2];  [3]
  1. Gladstone Inst. and Univ. of California, San Francisco, CA (United States). Center for Cell Circuitry (GC3)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Science (CNMS)
  3. Gladstone Inst. and Univ. of California, San Francisco, CA (United States). Center for Cell Circuitry (GC3); Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; National Institutes of Health (NIH); Netherlands Organization for Scientific Research (NWO)
OSTI Identifier:
1474451
Grant/Contract Number:  
AC05-00OR22725; S10 1S10OD017993-01A1; P30 AI027763; S10 RR028962; 019.153LW.028; R01AI109593; P01AI090935; OD006677; OD17181
Resource Type:
Accepted Manuscript
Journal Name:
Cell Systems
Additional Journal Information:
Journal Volume: 7; Journal Issue: 3; Journal ID: ISSN 2405-4712
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; stochastic noise; bursting; mathematical modeling; noise amplification; noise attenuation; nuclear export; single molecule RNA FISH; mRNA degradation; transcription; translation

Citation Formats

Hansen, Maike M. K., Desai, Ravi V., Simpson, Michael L., and Weinberger, Leor S. Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability. United States: N. p., 2018. Web. doi:10.1016/j.cels.2018.08.002.
Hansen, Maike M. K., Desai, Ravi V., Simpson, Michael L., & Weinberger, Leor S. Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability. United States. doi:10.1016/j.cels.2018.08.002.
Hansen, Maike M. K., Desai, Ravi V., Simpson, Michael L., and Weinberger, Leor S. Wed . "Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability". United States. doi:10.1016/j.cels.2018.08.002. https://www.osti.gov/servlets/purl/1474451.
@article{osti_1474451,
title = {Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability},
author = {Hansen, Maike M. K. and Desai, Ravi V. and Simpson, Michael L. and Weinberger, Leor S.},
abstractNote = {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 also 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.},
doi = {10.1016/j.cels.2018.08.002},
journal = {Cell Systems},
number = 3,
volume = 7,
place = {United States},
year = {2018},
month = {9}
}

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