Stochastic pausing at latent HIV-1 promoters generates transcriptional bursting

Tantale, Katjana; García-Oliver, Encar; Robert, Marie-Cécile; L'Hostis, A.; Yang, Yueyuxiao; Tsanov, Nikolay; Topno, Rachel; Gostan, Thierry; Kozulic-Pirher, Alja; Basu-Shrivastava, Meenakshi; Mukherjee, Kamalika; Slaninova, Vera; Andrau, Jean-Christophe; Mueller, Florian; Basyuk, Eugénia; Radulescu, Ovidiu; Bertrand, Édouard

doi:10.1038/s41467-021-24462-5

Cited by 42 publications

(69 citation statements)

References 70 publications

(129 reference statements)

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“…This subpopulation is also higher in mCherry expression, compared to the total double-positive population. The reversal of double-positive cells after sorting may reflect the intrinsically stochastic transcription of HIV-1 ( 84 – 86 ). Latent cell lines are notoriously sensitive to cellular stresses, which cause reactivation ( 87 – 89 ).…”

Section: Discussionmentioning

confidence: 99%

A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

Röling

Sisakht

et al. 2021

mBio

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Section: Discussionmentioning

confidence: 99%

A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

Röling

Sisakht

et al. 2021

mBio

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“…Nevertheless, stochastic fluctuations of the Tat protein appear to be sufficient to determine the fate of viral transcription independently from the cellular activation state [123]. Furthermore, RNA polymerase II pausing, another process potentially impacting HIV-1 latency reversal, appears to be a stochastic phenomenon, with only a small percentage of transcripts pausing even in the absence of Tat, therefore further sustaining the hypothesis of randomly occurring events regulating HIV-1 transition from latency to active replication [124].…”

Section: Cellular Transcription Factors Mediating Viral Transcription...mentioning

confidence: 77%

Fighting HIV-1 Persistence: At the Crossroads of “Shoc-K and B-Lock”

et al. 2021

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Despite the success of highly active antiretroviral therapy (HAART), integrated HIV-1 proviral DNA cannot be eradicated from an infected individual. HAART is not able to eliminate latently infected cells that remain invisible to the immune system. Viral sanctuaries in specific tissues and immune-privileged sites may cause residual viral replication that contributes to HIV-1 persistence. The “Shock or Kick, and Kill” approach uses latency reversing agents (LRAs) in the presence of HAART, followed by cell-killing due to viral cytopathic effects and immune-mediated clearance. Different LRAs may be required for the in vivo reactivation of HIV-1 in different CD4+ T cell reservoirs, leading to the activation of cellular transcription factors acting on the integrated proviral HIV-1 LTR. An important requirement for LRA drugs is the reactivation of viral transcription and replication without causing a generalized immune activation. Toll-like receptors, RIG-I like receptors, and STING agonists have emerged recently as a new class of LRAs that augment selective apoptosis in reactivated T lymphocytes. The challenge is to extend in vitro observations to HIV-1 positive patients. Further studies are also needed to overcome the mechanisms that protect latently infected cells from reactivation and/or elimination by the immune system. The Block and Lock alternative strategy aims at using latency promoting/inducing agents (LPAs/LIAs) to block the ability of latent proviruses to reactivate transcription in order to achieve a long term lock down of potential residual virus replication. The Shock and Kill and the Block and Lock approaches may not be only alternative to each other, but, if combined together (one after the other), or given all at once [namely “Shoc-K(kill) and B(block)-Lock”], they may represent a better approach to a functional cure.

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“…Briefly, upon initiation of HIV transcription, the initiated transcripts form a stem-loop structure referred to as the transactivating response region (TAR), which leads to promoter proximal pausing by RNAPII [64]. HIV encodes its own transcriptional transactivator (Tat), which recruits P-TEFb to the transcriptional start site [65, 66] where it releases paused RNAPII to enable elongation and the generation of a full-length transcript [6,36,67]. HIV exhibits bimodal activation under basal conditions [68] and following stimulation with TNF [69], and therefore we were interested to see to what extent positive feedback contributed to this observation.…”

Section: Resultsmentioning

confidence: 99%

A transcriptional cycling model recapitulates chromatin-dependent features of noisy inducible transcription

Bullock

Moreno-Martinez

Miller‐Jensen

2022

Preprint

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Activation of gene expression in response to environmental cues results in substantial phenotypic heterogeneity between cells that can impact a wide range of outcomes including differentiation, viral activation, and drug resistance. An important source of gene expression noise is transcriptional bursting, or the observation that transcripts are produced during infrequent bursts of promoter activity. Chromatin accessibility, which regulates assembly of polymerase complexes on promoters, impacts transcriptional bursting, suggesting that how an activating signal affects transcriptional noise will depend on the initial chromatin state at the promoter. To explore this possibility, we simulated transcriptional activation using a transcriptional cycling model with three promoter states that represent chromatin remodeling, polymerase binding and pause release. We initiated this model over a large parameter range representing target genes with different chromatin environments, and found that, upon increasing the polymerase pause release rate to activate transcription, changes in gene expression noise varied significantly across initial promoter states. This model captured phenotypic differences in activation of latent HIV viruses integrated at different chromatin locations and mediated by the transcription factor NF-kB. Activating transcription in the model via increasing one or more of the transcript production rates, as occurs following NF-kB activation, reproduced experimentally measured transcript distributions for four different latent HIV viruses, as well as the bimodal pattern of HIV protein expression that leads to a subset of reactivated virus. Importantly, the parameter ‘activation path’ differentially affected gene expression noise, and ultimately viral activation, in line with experimental observations. This work demonstrates how upstream signaling pathways can be connected to biological processes that underlie transcriptional bursting, resulting in target gene-specific noise profiles following stimulation of a single upstream pathway.

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Stochastic pausing at latent HIV-1 promoters generates transcriptional bursting

Cited by 42 publications

References 70 publications

A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

Fighting HIV-1 Persistence: At the Crossroads of “Shoc-K and B-Lock”

A transcriptional cycling model recapitulates chromatin-dependent features of noisy inducible transcription

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