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Transient-mediated fate determination in a transcriptional circuit of HIV

Leor Weinberger¹, Roy D. Dar² & Michael Simpson³

Correspondence: (Login to view email address)

1. University of California, San Diego, Dept. of Chemistry and Biochemistry
2. Oak Ridge National Laboratory/University of Tennessee,
3. Oak Ridge National Laboratory/University of Tennessee, Molecular-Scale Engineering

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Document Type:

Manuscript

Date:

Received 30 September 2007 17:17 UTC; Posted 01 October 2007

Subjects:

Biotechnology, Genetics & Genomics, Molecular Cell Biology

Tags:

• transcriptional noise
• gene circuit fluctuation analysis
• HIV
• Tat
• latency
• monostability
• bistability

Abstract:

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 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 transients 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 ~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.

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License:

This document is licensed to the public under the Creative Commons Attribution 2.5 License

How to cite this document:

Weinberger, Leor, Dar, Roy, and Simpson, Michael. Transient-mediated fate determination in a transcriptional circuit of HIV. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2007.1198.1> (2007)

Version info:

Published version:

10.1038/ng.116 (Peer Reviewed) Published in Nature Genetics 40, 466 - 470 (2008)

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