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Title: Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels

Abstract

Recent analysis demonstrates that the HIV-1 Long Terminal Repeat (HIV LTR) promoter exhibits a range of possible transcriptional burst sizes and frequencies for any mean-expression level. However, these results have also been interpreted as demonstrating that cell-tocell expression variability (noise) and mean are uncorrelated, a significant deviation from previous results. Here, we re-examine the available mRNA and protein abundance data for the HIV LTR and find that noise in mRNA and protein expression scales inversely with the mean along analytically predicted transcriptional burst-size manifolds. We then experimentally perturb transcriptional activity to test a prediction of the multiple burst-size model: that increasing burst frequency will cause mRNA noise to decrease along given burst-size lines as mRNA levels increase. In conclusion, the data show that mRNA and protein noise decrease as mean expression increases, supporting the canonical inverse correlation between noise and mean.

Authors:
 [1];  [2];  [3];  [4];  [5];  [2];  [6]
  1. Univ. of Illinois Urbana-Champaign, Urbana, IL (United States)
  2. Univ. of Pennsylvania, Philadelphia, PA (United States)
  3. Univ. of Delaware, Newark, DE (United States)
  4. Rockefeller Univ., New York, NY (United States)
  5. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  6. Gladstone Institutes, San Francisco, CA (United States); Univ. of California San Francisco, San Francisco, CA (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Joint Institute for Biological Sciences (JIBS)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1279452
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 7; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; HIV; messenger RNA; cloning; fluorescent in situ hybridization; gene expression; HIV-1; human genomics; protein expression

Citation Formats

Dar, Roy, Shaffer, Sydney M., Singh, Abhyudai, Razooky, Brandon S., Simpson, Michael L., Raj, Arjun, and Weinberger, Leor S. Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels. United States: N. p., 2016. Web. https://doi.org/10.1371/journal.pone.0158298.
Dar, Roy, Shaffer, Sydney M., Singh, Abhyudai, Razooky, Brandon S., Simpson, Michael L., Raj, Arjun, & Weinberger, Leor S. Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels. United States. https://doi.org/10.1371/journal.pone.0158298
Dar, Roy, Shaffer, Sydney M., Singh, Abhyudai, Razooky, Brandon S., Simpson, Michael L., Raj, Arjun, and Weinberger, Leor S. Thu . "Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels". United States. https://doi.org/10.1371/journal.pone.0158298. https://www.osti.gov/servlets/purl/1279452.
@article{osti_1279452,
title = {Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels},
author = {Dar, Roy and Shaffer, Sydney M. and Singh, Abhyudai and Razooky, Brandon S. and Simpson, Michael L. and Raj, Arjun and Weinberger, Leor S.},
abstractNote = {Recent analysis demonstrates that the HIV-1 Long Terminal Repeat (HIV LTR) promoter exhibits a range of possible transcriptional burst sizes and frequencies for any mean-expression level. However, these results have also been interpreted as demonstrating that cell-tocell expression variability (noise) and mean are uncorrelated, a significant deviation from previous results. Here, we re-examine the available mRNA and protein abundance data for the HIV LTR and find that noise in mRNA and protein expression scales inversely with the mean along analytically predicted transcriptional burst-size manifolds. We then experimentally perturb transcriptional activity to test a prediction of the multiple burst-size model: that increasing burst frequency will cause mRNA noise to decrease along given burst-size lines as mRNA levels increase. In conclusion, the data show that mRNA and protein noise decrease as mean expression increases, supporting the canonical inverse correlation between noise and mean.},
doi = {10.1371/journal.pone.0158298},
journal = {PLoS ONE},
number = 7,
volume = 11,
place = {United States},
year = {2016},
month = {7}
}

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Works referenced in this record:

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    journal, January 2017

    • Nicolas, Damien; Phillips, Nick E.; Naef, Felix
    • Molecular BioSystems, Vol. 13, Issue 7
    • DOI: 10.1039/c7mb00154a

    Fine-tuning of noise in gene expression with nucleosome remodeling
    journal, June 2018

    • Megaridis, Melina R.; Lu, Yiyang; Tevonian, Erin N.
    • APL Bioengineering, Vol. 2, Issue 2
    • DOI: 10.1063/1.5021183

    Discontinuous transcription
    journal, January 2018


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    journal, December 2019

    • Friedrich, Dhana; Friedel, Laura; Finzel, Ana
    • Molecular Systems Biology, Vol. 15, Issue 12
    • DOI: 10.15252/msb.20199068