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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 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:
Journal Article: 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.
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. doi:10.1371/journal.pone.0158298.
Dar, Roy, Shaffer, Sydney M., Singh, Abhyudai, Razooky, Brandon S., Simpson, Michael L., Raj, Arjun, and Weinberger, Leor S. 2016. "Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels". United States. doi: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
}

Journal Article:
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  • Analysis of noise in gene expression has proven a powerful approach for analyzing gene regulatory architecture. To probe the regulatory mechanisms controlling expression of HIV-1, we analyze noise in gene-expression from HIV-1 s long terminal repeat (LTR) promoter at different HIV-1 integration sites across the human genome. Flow cytometry analysis of GFP expression from the HIV-1 LTR shows high variability (noise) at each integration site. Notably, the measured noise levels are inconsistent with constitutive gene expression models. Instead, quantification of expression noise indicates that HIV-1 gene expression occurs through randomly timed bursts of activity from the LTR and that eachmore » burst generates an average of 2 10 mRNA transcripts before the promoter returns to an inactive state. These data indicate that transcriptional bursting can generate high variability in HIV-1 early gene products, which may critically influence the viral fate-decision between active replication and proviral latency.« less
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