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Title: Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean

Abstract

Fundamental to biological decision-making is the ability to generate bimodal expression patterns where two alternate expression states simultaneously exist. Here in this study, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV’s fate decision between active replication and viral latency. We find that the HIV Tat protein manipulates the intrinsic toggling of HIV’s promoter, the LTR, to generate bimodal ON-OFF expression, and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit’s non-cooperative ‘non-latching’ feedback architecture is optimized to slow the promoter’s toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that non-latching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean-expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV’s decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuitsmore » may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.« less

Authors:
 [1];  [2];  [3];  [2]; ORCiD logo [4]; ORCiD logo [5]
  1. Rockefeller Univ., New York, NY (United States). Lab. of Virology and Infectious Disease; Gladstone Institutes (Virology and Immunology), San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Science (CNMS); Univ. of Tennessee, Knoxville, TN (United States). Bredesen Center for Interdisciplinary Research and Graduate Education
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Gladstone Institutes (Virology and Immunology), San Francisco, CA (United States)
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Science (CNMS); Univ. of Tennessee, Knoxville, TN (United States). Bredesen Center for Interdisciplinary Research and Graduate Education
  5. Gladstone Institutes (Virology and Immunology), San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics; Univ. of California, San Francisco, CA (United States). QB3: California Inst. of Quantitative Biosciences; Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1407734
DOE Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article
Resource Relation:
Journal Name: PLoS biology (Online); Journal Volume: 15; Journal Issue: 10
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Razooky, Brandon S., Cao, Youfang, Hansen, Maike M. K., Perelson, Alan S., Simpson, Michael L., and Weinberger, Leor S.. Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean. United States: N. p., 2017. Web. doi:10.1371/journal.pbio.2000841.
Razooky, Brandon S., Cao, Youfang, Hansen, Maike M. K., Perelson, Alan S., Simpson, Michael L., & Weinberger, Leor S.. Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean. United States. doi:10.1371/journal.pbio.2000841.
Razooky, Brandon S., Cao, Youfang, Hansen, Maike M. K., Perelson, Alan S., Simpson, Michael L., and Weinberger, Leor S.. Wed . "Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean". United States. doi:10.1371/journal.pbio.2000841. https://www.osti.gov/servlets/purl/1407734.
@article{osti_1407734,
title = {Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean},
author = {Razooky, Brandon S. and Cao, Youfang and Hansen, Maike M. K. and Perelson, Alan S. and Simpson, Michael L. and Weinberger, Leor S.},
abstractNote = {Fundamental to biological decision-making is the ability to generate bimodal expression patterns where two alternate expression states simultaneously exist. Here in this study, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV’s fate decision between active replication and viral latency. We find that the HIV Tat protein manipulates the intrinsic toggling of HIV’s promoter, the LTR, to generate bimodal ON-OFF expression, and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit’s non-cooperative ‘non-latching’ feedback architecture is optimized to slow the promoter’s toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that non-latching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean-expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV’s decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuits may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.},
doi = {10.1371/journal.pbio.2000841},
journal = {PLoS biology (Online)},
number = 10,
volume = 15,
place = {United States},
year = {Wed Oct 18 00:00:00 EDT 2017},
month = {Wed Oct 18 00:00:00 EDT 2017}
}