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PLoS Biol. 2017 Oct 18;15(10):e2000841. doi: 10.1371/journal.pbio.2000841. eCollection 2017 Oct.

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

Author information

1
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America.
2
The Gladstone Institutes (Virology and Immunology), San Francisco, California, United States of America.
3
Biophysics Graduate Group, University of California, San Francisco, San Francisco, California, United Sates of America.
4
Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee, United States of America.
5
Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, Tennessee, United States of America.
6
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
7
Center for Nonlinear Studies (CNLS), Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
8
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
9
QB3: California Institute of Quantitative Biosciences, University of California, San Francisco, San Francisco, California, United States of America.
10
Department of Pharmaceutical Chemistry University of California, San Francisco, San Francisco, California, United States of America.

Abstract

Fundamental to biological decision-making is the ability to generate bimodal expression patterns where 2 alternate expression states simultaneously exist. Here, 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 transactivator of transcription (Tat) protein manipulates the intrinsic toggling of HIV's promoter, the long terminal repeat (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 noncooperative "nonlatching" 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 nonlatching 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.

PMID:
29045398
PMCID:
PMC5646755
DOI:
10.1371/journal.pbio.2000841
[Indexed for MEDLINE]
Free PMC Article

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