Transient-mediated fate determination in a transcriptional circuit of HIV

Abstract

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.