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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]
+ Show Author Affiliations
  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 Laboratory (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. doi:10.1371/journal.pone.0158298.
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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
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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.
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@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 = {Thu Jul 28 00:00:00 EDT 2016},
month = {Thu Jul 28 00:00:00 EDT 2016}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1371/journal.pone.0158298
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Cited by: 37 works
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Works referenced in this record:

Genetic Determinants and Cellular Constraints in Noisy Gene Expression
journal, December 2013

Markovian Modeling of Gene-Product Synthesis
journal, October 1995

Orthogonal control of expression mean and variance by epigenetic features at different genomic loci
journal, May 2015

  • Dey, Siddharth S.; Foley, Jonathan E.; Limsirichai, Prajit
  • Molecular Systems Biology, Vol. 11, Issue 5
  • DOI: 10.15252/msb.20145704

Transcriptional Bursting from the HIV-1 Promoter Is a Significant Source of Stochastic Noise in HIV-1 Gene Expression
journal, April 2010

Lentiviral Vectors to Study Stochastic Noise in Gene Expression
book, January 2011

Transcriptional burst frequency and burst size are equally modulated across the human genome
journal, October 2012

  • Dar, R. D.; Razooky, B. S.; Singh, A.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 43
  • DOI: 10.1073/pnas.1213530109

Screening for noise in gene expression identifies drug synergies
journal, June 2014

HIV Promoter Integration Site Primarily Modulates Transcriptional Burst Size Rather Than Frequency
journal, September 2010

Stochastic mRNA Synthesis in Mammalian Cells
journal, September 2006

Imaging individual mRNA molecules using multiple singly labeled probes
journal, September 2008

  • Raj, Arjun; van den Bogaard, Patrick; Rifkin, Scott A.
  • Nature Methods, Vol. 5, Issue 10
  • DOI: 10.1038/nmeth.1253

Dynamics of protein noise can distinguish between alternate sources of gene‐expression variability
journal, January 2012

  • Singh, Abhyudai; Razooky, Brandon S.; Dar, Roy D.
  • Molecular Systems Biology, Vol. 8, Issue 1
  • DOI: 10.1038/msb.2012.38

Markovian Modeling of Gene-Product Synthesis
journal, October 1995

Transcriptional Bursting from the HIV-1 Promoter Is a Significant Source of Stochastic Noise in HIV-1 Gene Expression
journal, April 2010

Stochasticity in Transcriptional Regulation: Origins, Consequences, and Mathematical Representations
journal, December 2001

Dynamics of protein noise can distinguish between alternate sources of gene‐expression variability
journal, January 2012

  • Singh, Abhyudai; Razooky, Brandon S.; Dar, Roy D.
  • Molecular Systems Biology, Vol. 8, Issue 1
  • DOI: 10.1038/msb.2012.38

Imaging individual mRNA molecules using multiple singly labeled probes
journal, September 2008

  • Raj, Arjun; van den Bogaard, Patrick; Rifkin, Scott A.
  • Nature Methods, Vol. 5, Issue 10
  • DOI: 10.1038/nmeth.1253

Transcriptional burst frequency and burst size are equally modulated across the human genome
journal, October 2012

  • Dar, R. D.; Razooky, B. S.; Singh, A.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 43
  • DOI: 10.1073/pnas.1213530109

Genetic Determinants and Cellular Constraints in Noisy Gene Expression
journal, December 2013

Screening for noise in gene expression identifies drug synergies
journal, June 2014

Chance Fluctuations in mRNA Output in Mammalian Cells
journal, September 2006

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    Works referencing / citing this record:

    Simulating multiple faceted variability in single cell RNA sequencing
    journal, June 2019

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    • 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

    3’-5’ crosstalk contributes to transcriptional bursting
    posted_content, December 2020

    • Cavallaro, Massimo; Walsh, Mark D.; Jones, Matt
    • bioRxiv
    • DOI: 10.1101/514174

    Stochastic transcription in the p53‐mediated response to DNA damage is modulated by burst frequency
    journal, December 2019

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

    Discontinuous transcription
    book, December 2015

    3 ′-5 ′ crosstalk contributes to transcriptional bursting
    journal, February 2021

    Cell Size-Based Decision-Making of a Viral Gene Circuit
    journal, December 2018

    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

    Stochastic gene expression is optimized to drive developmental self-organization
    journal, April 2019

    • Giri, Ritika; Papadopoulos, Dimitrios K.; Posadas, Diana M.
    • DOI: 10.1101/546911
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