Transient-mediated fate determination in a transcriptional circuit of HIV

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Nature Genetics

DOI:https://doi.org/10.1038/ng.116· OSTI ID:940330

Weinberger, Leor S. ^[1]; Dar, Roy D. ^[2]; Simpson, Michael L ^[3]

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1. University of California, San Diego
2. University of Tennessee, Knoxville (UTK)
3. ORNL

Steady-state behavior and bistability have been proposed as mechanisms for decision-making in gene circuits1-3. However, transient gene expression has also been proposed to control cell fate4, 5 with the decision arbitrated by the lifetime of the expression transient. Here, we report that transcriptional positive-feedback plays a critical role in determining HIV infected cell-fate by extending the duration of Tat expression transients6, 7 far beyond what protein half-life modulation can achieve. To directly quantify feedback strength and its effects on the duration of Tat transcriptional pulses, we exploit the noise inherent to gene-expression and measure shifts in the autocorrelation of expression noise. The results indicate that transcriptional positive-feedback extends the single-cell Tat expression lifetime by 2-to 6-fold for both minimal Tat circuits and full-length, actively-replicating HIV-1. Importantly, 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 appears to modulate transient expression lifetime and thereby control cell-fate in HIV.

• Research Organization: Oak Ridge National Laboratory (ORNL); Center for Nanophase Materials Sciences
• Sponsoring Organization: SC USDOE - Office of Science (SC)
• DOE Contract Number: AC05-00OR22725
• OSTI ID: 940330
• Journal Information: Nature Genetics, Journal Name: Nature Genetics Journal Issue: 4 Vol. 40
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
AIDS VIRUS
DECISION MAKING
FEEDBACK
GENES
HALF-LIFE
LIFETIME
MODULATION
PROBABILITY
PROTEINS
TRANSIENTS