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Stochastic pausing at latent HIV-1 promoters generates transcriptional bursting

Authors :
A. Kozulic-Pirher
Marie-Cécile Robert
E. Garcia-Olivier
M. Basu
Edouard Bertrand
Ovidiu Radulescu
Katjana Tantale
A. L'Hostis
Jean-Christophe Andrau
Thierry Gostan
Y. Yang
F. Muller
Eugenia Basyuk
Institut de Génétique Moléculaire de Montpellier (IGMM)
Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

SummaryPromoter-proximal polymerase pausing is a key process regulating gene expression. In latent HIV-1 cells, it prevents viral transcription and is essential for latency maintenance, while in acutely infected cells the viral factor Tat releases paused polymerase to induce viral expression. Pausing is fundamental for HIV-1, but how it contributes to bursting and stochastic viral reactivation is unclear. Here, we performed single molecule imaging of HIV-1 transcription, and we developed a quantitative analysis method that manages multiple time scales from seconds to days, and that rapidly fits many models of promoter dynamics. We found that RNA polymerases enter a long-lived pause at latent HIV-1 promoters (>20 minutes), thereby effectively limiting viral transcription. Surprisingly and in contrast to current models, pausing appears stochastic and not obligatory, with only a small fraction of the polymerases undergoing long-lived pausing in absence of Tat. One consequence of stochastic pausing is that HIV-1 transcription occurs in bursts in latent cells, thereby facilitating latency exit and providing a rationale for the stochasticity of viral rebounds.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....3644279dedc69bf8626431e32c402cbb
Full Text :
https://doi.org/10.1101/2020.08.25.265413