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 »
- Authors:
-
[4];
[5]
- 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
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Gladstone Institutes (Virology and Immunology), 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
- 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 Laboratory (ORNL), Oak Ridge, TN (United States); Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Heath (NIH); National Science Foundation (NSF); Netherlands Organization of Scientific Research (NWO); W.M. Keck Foundation; Alfred P. Sloan Research Foundation; National Institutes of Health (NIH)
- OSTI Identifier:
- 1407734
- Alternate Identifier(s):
- OSTI ID: 1418767
- Report Number(s):
- LA-UR-17-24854
Journal ID: ISSN 1545-7885
- Grant/Contract Number:
- AC05-00OR22725; AC52-06NA25396; OD006677; R01OD011095; ACI-1053575; 019.153LW.028
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Biology (Online)
- Additional Journal Information:
- Journal Name: PLoS Biology (Online); Journal Volume: 15; Journal Issue: 10; Journal ID: ISSN 1545-7885
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science
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. https://doi.org/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. https://doi.org/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}
}
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