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

• Published in: PLoS biology Vol. 15; no. 10; p. e2000841
• Main Authors: Razooky, Brandon S, Cao, Youfang, Hansen, Maike M K, Perelson, Alan S, Simpson, Michael L, Weinberger, Leor S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.10.2017; Public Library of Science (PLoS)
• Subjects: 60 APPLIED LIFE SCIENCES; Active control; Algorithms; BASIC BIOLOGICAL SCIENCES; Biological evolution; Biological Science; Biology; Biology and Life Sciences; Biophysics; Chemistry; Circuits; Computer applications; Data collection; Decision making; Decoupling; Engineering and Technology; Feedback; Feedback circuits; Feedback, Physiological; Fitness; Flow Cytometry; Funding; Gene expression; Gene Expression Regulation, Viral - genetics; Graduate studies; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; HIV; HIV Infections - virology; HIV Long Terminal Repeat - genetics; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Humans; Hypotheses; Immunology; Interdisciplinary aspects; Jurkat Cells; Laboratories; Latency; Long terminal repeat; Materials science; Mathematical models; Medicine and Health Sciences; Microscopy, Confocal; Models, Genetic; Noise; Positive feedback; Promoter Regions, Genetic - genetics; Protein expression; Proteins; Replication; Reproductive fitness; Research and Analysis Methods; Robustness (mathematics); Single-Cell Analysis - methods; Software; Stochastic Processes; Stochasticity; tat Gene Products, Human Immunodeficiency Virus - genetics; Tat protein; Transcription; Transcription, Genetic; Virology; Virus Latency; Viruses; New York; San Francisco California; California; New Mexico; United States > US; Tennessee
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.2000841

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.