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

Razooky, Brandon S.; Cao, Youfang; Hansen, Maike M.  K.; Perelson, Alan S.; Simpson, Michael L.; Weinberger, Leor S.

doi:10.1371/journal.pbio.2000841

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

Journal Article · Wed Oct 18 00:00:00 EDT 2017 · PLoS Biology (Online)

DOI:https://doi.org/10.1371/journal.pbio.2000841· OSTI ID:1407734

Razooky, Brandon S. ^[1]; Cao, Youfang ^[2]; Hansen, Maike M. K. ^[3]; Perelson, Alan S. ^[2]; ^[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

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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: Alfred P. Sloan Research Foundation; National Institutes of Health; National Institutes of Heath (NIH); National Science Foundation (NSF); Netherlands Organization of Scientific Research (NWO); USDOE; USDOE Office of Science (SC); W.M. Keck Foundation

Grant/Contract Number:: AC05-00OR22725; AC52-06NA25396

OSTI ID:: 1407734

Alternate ID(s):: OSTI ID: 1418767

Report Number(s):: LA-UR--17-24854

Journal Information:: PLoS Biology (Online), Journal Name: PLoS Biology (Online) Journal Issue: 10 Vol. 15; ISSN 1545-7885

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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