Transient-mediated fate determination in a transcriptional circuit of HIV.
Steady-state behavior and bistability have been proposed as mechanisms for decision making in gene circuits. However, transient gene expression has also been proposed to control cell fate, with the decision arbitrated by the duration of a transient gene expression pulse. Here, using an HIV-1 model system, we directly quantify transcriptional feedback strength and its effects on both the duration of HIV-1 Tat transcriptional pulses and the fate of HIV-infected cells. By measuring shifts in the autocorrelation of noise inherent to gene expression, we found that transcriptional positive feedback extends the single-cell Tat expression lifetime two- to sixfold for both minimal Tat circuits and full length, actively replicating HIV-1. Notably, artificial weakening of Tat positive feedback shortened the duration of Tat expression transients and biased the probability in favor of latency. Thus, transcriptional positive feedback can modulate transient expression lifetime to a greater extent than protein half-life modulation, and it has a critical role in the cell-fate decision in HIV.
Weinberger
Leor S
LS
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive 0314, La Jolla, California 92093, USA. lsw@ucsd.edu
Dar
Roy D
RD
Simpson
Michael L
ML
D015153:Blotting, Western; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D049452:Green Fluorescent Proteins; D006678:HIV / Q000502:physiology*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017735:Virus Latency; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; C485184:enhanced green fluorescent protein; D054322:tat Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins