Influenza Virus Mounts a Two-Pronged Attack on Host RNA Polymerase II Transcription

Bauer, David L.V.; Tellier, Michael; Martínez-Alonso, Maira; Nojima, Takayuki; Proudfoot, Nick J.; Murphy, Shona; Fodor, Ervin

doi:10.1016/j.celrep.2018.04.047

Cited by 88 publications

(139 citation statements)

References 74 publications

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“…While a combination of viral factors could be responsible for this global shutoff of host transcription, our data suggest that NS1 might be associated with this phenomenon. There is evidence in the literature that IAV infection results in reduced host transcription and mRNA processing by inhibiting the host RNA polymerase II (Pol II) function (60,61). Related to this, a recent study found that several strains of IAV elicit global deregulation of Poll II transcription termination by impairing 3=-end cleavage and termination, and this effect was dependent on NS1 expression (62).…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Ramos

Smith

Ruf-Zamojski

et al. 2019

J Virol

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Early interactions of influenza A virus (IAV) with respiratory epithelium might determine the outcome of infection. The study of global cellular innate immune responses often masks multiple aspects of the mechanisms by which populations of cells work as organized and heterogeneous systems to defeat virus infection, and how the virus counteracts these systems. In this study, we experimentally dissected the dynamics of IAV and human epithelial respiratory cell interaction during early infection at the single-cell level. We found that the number of viruses infecting a cell (multiplicity of infection [MOI]) influences the magnitude of virus antagonism of the host innate antiviral response. Infections performed at high MOIs resulted in increased viral gene expression per cell and stronger antagonist effect than infections at low MOIs. In addition, single-cell patterns of expression of interferons (IFN) and IFN-stimulated genes (ISGs) provided important insights into the contributions of the infected and bystander cells to the innate immune responses during infection. Specifically, the expression of multiple ISGs was lower in infected than in bystander cells. In contrast with other IFNs, IFN lambda 1 (IFNL1) showed a widespread pattern of expression, suggesting a different cell-to-cell propagation mechanism more reliant on paracrine signaling. Finally, we measured the dynamics of the antiviral response in primary human epithelial cells, which highlighted the importance of early innate immune responses at inhibiting virus spread. IMPORTANCE Influenza A virus (IAV) is a respiratory pathogen of high importance to public health. Annual epidemics of seasonal IAV infections in humans are a significant public health and economic burden. IAV also causes sporadic pandemics, which can have devastating effects. The main target cells for IAV replication are epithelial cells in the respiratory epithelium. The cellular innate immune responses induced in these cells upon infection are critical for defense against the virus, and therefore, it is important to understand the complex interactions between the virus and the host cells. In this study, we investigated the innate immune response to IAV in the respiratory epithelium at the single-cell level, providing a better understanding on how a population of epithelial cells functions as a complex system to orchestrate the response to virus infection and how the virus counteracts this system.

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Section: Discussionmentioning

confidence: 99%

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Ramos

Smith

Ruf-Zamojski

et al. 2019

J Virol

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“…Defective termination of Pol II transcription in response to cell stress has been reported (11)(12)(13)(14)(15). During normal termination of mRNA transcription in mammalian cells, the polymerase accumulates just downstream of the 3= end of most genes, which can be detected in Pol II ChIP-seq and native elongating transcript sequencing (NET-seq) assays (16)(17)(18).…”

mentioning

confidence: 99%

Heat Shock Causes a Reversible Increase in RNA Polymerase II Occupancy Downstream of mRNA Genes, Consistent with a Global Loss in Transcriptional Termination

Cardiello

Goodrich

Kugel

2018

Molecular and Cellular Biology

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Cellular transcriptional programs are tightly controlled but can profoundly change in response to environmental challenges or stress. Here we describe global changes in mammalian RNA polymerase II (Pol II) occupancy at mRNA genes in response to heat shock and after recovery from the stress. After a short heat shock, Pol II occupancy across thousands of genes decreased, consistent with widespread transcriptional repression, whereas Pol II occupancy increased at a small number of genes in a manner consistent with activation. Most striking, however, was loss of the Pol II peak near the 3' ends of mRNA genes, coupled to a gain in polymerase occupancy extending tens of kilobases downstream of 3' ends. Typical patterns of 3' end occupancy were largely restored 60 min after cells returned to normal growth temperatures. These changes in polymerase occupancy revealed a heat shock-induced loss of normal termination, which was potent, global, and reversible. The occupancy of the termination factor CPSF73 at the 3' ends of representative genes was reduced after heat shock, suggesting a mechanism for impaired termination. The data support a model in which heat shock induces widespread repression of transcriptional initiation and loss of transcription termination, which reverses as cells return to homeostasis.

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“…DoG genes showed significant enrichments for specific gene ontologies (GOs), including translation initiation and ribosome biogenesis, viral process, response to stress, mitochondrial gene expression, and chromatin organization ( Figure 3D, Figure S3B). The appearance of stress-related and viral-related GOs is notable given precedents for DoG transcription triggered upon environmental stresses and viral infections (Bauer et al, 2018;Cardiello et al, 2018;Hennig et al, 2018;Vilborg et al, 2015;Vilborg et al, 2017).…”

Section: Dog Transcription Affects a Specific Subset Of Stress-responmentioning

confidence: 99%

“…DoG genes were enriched for GOs related to protein translation and response to cellular stress, consistent with our observation of a broad cellular response characterized by increased ribosome biogenesis, protein translation, mitochondrial respiration, and ATP synthesis ( Figure 6). Interestingly, DoG transcription has been observed in response to a range of cellular stresses including oxidative stress (Giannakakis et al, 2015;Vilborg et al, 2017), heat shock (Cardiello et al, 2018;Vilborg et al, 2017), and osmotic stress (Vilborg et al, 2015;Vilborg et al, 2017), in addition to viral infections (Bauer et al, 2018;Heinz et al, 2018;Hennig et al, 2018). However, the mechanisms underlying DoG transcription are not clear.…”

Section: Pladb-induced Transcriptional Alterations Resemble Other Strmentioning

confidence: 99%

SF3B1-targeted Splicing Inhibition Triggers Global Alterations in Transcriptional Dynamics and R-Loop Metabolism

Castillo-Guzman

Hartono

Sanz

et al. 2020

Preprint

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Efficient co-transcriptional splicing is thought to suppress the formation of genome-destabilizing R-loops upon interaction between nascent RNA and the DNA template. Inhibition of the SF3B splicing complex using Pladienolide B (PladB) in human K562 cells caused widespread intron retention and nearly 2,000 instances of R-loops gains. However, only minimal overlap existed between these events, arguing that unspliced introns do not cause excessive R-loops. R-loop gains were instead driven by readthrough transcription resulting from loss of transcription termination over a subset of stress-response genes, defining a new class of aberrant "downstream of genes" (DoG) R-loops. Such DoG R-loops were temporally and spatially uncoupled from loci experiencing DNA damage. Unexpectedly, the predominant response to splicing inhibition was a global R-loop loss resulting from accumulation of promoter-proximal paused RNA polymerases and defective elongation. Thus, SF3B1-targeted splicing inhibition triggered profound alterations in transcriptional dynamics, leading to unexpected disruptions in the global R-loop landscape. HIGHLIGHTS • Intron retention caused by SF3B1 inhibition does not lead to excessive R-loops • A subset of genes shows readthrough transcription and accompanying R-loop gains • SF3B1 inhibition causes broad reduction in nascent transcription and R-loop loss • R-loop gains and DNA damage are temporally and spatially uncoupled RNAPII RNA +PladB PAS zZz Promoter pausing Elongation R-loops downstream of gene PAS zZz R-loops Txn read through DoG R-loops Promoter pausing Elongation No R-loop PAS zZz

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Influenza Virus Mounts a Two-Pronged Attack on Host RNA Polymerase II Transcription

Cited by 88 publications

References 74 publications

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Heat Shock Causes a Reversible Increase in RNA Polymerase II Occupancy Downstream of mRNA Genes, Consistent with a Global Loss in Transcriptional Termination

SF3B1-targeted Splicing Inhibition Triggers Global Alterations in Transcriptional Dynamics and R-Loop Metabolism

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