1. Chromosomes and Gene Expression

Viral-induced alternative splicing of host genes promotes influenza replication

  1. Matthew G Thompson
  2. Mark Dittmar
  3. Michael J Mallory
  4. Prasanna Bhat
  5. Max B Ferretti
  6. Beatriz MA Fontoura
  7. Sara Cherry
  8. Kristen W Lynch  Is a corresponding author
  1. University of Pennsylvania, United States
  2. UT Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.55500
Share this article
Cite this article
  1. Matthew G Thompson
  2. Mark Dittmar
  3. Michael J Mallory
  4. Prasanna Bhat
  5. Max B Ferretti
  6. Beatriz MA Fontoura
  7. Sara Cherry
  8. Kristen W Lynch
(2020)
Viral-induced alternative splicing of host genes promotes influenza replication
eLife 9:e55500.
https://doi.org/10.7554/eLife.55500
  2. Download BibTeX
  3. Download .RIS

Abstract

Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here we show that infection of human lung epithelial cells with Influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. While these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, in several cases, specific inhibition of the IAV-induced splicing pattern also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein required for efficient splicing of the IAV M transcript in nuclear speckles. Finally, we find an increase in hnRNP K in nuclear speckles upon IAV infection, which may alter accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.

Data availability

Sequencing data have been deposited in GEO under accession code GSE142499

The following data sets were generated

Article and author information

Author details

  1. Matthew G Thompson

    Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Mark Dittmar

    Pathology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Michael J Mallory

    Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Prasanna Bhat

    Cell Biology, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Max B Ferretti

    Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Beatriz MA Fontoura

    Cell Biology, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Sara Cherry

    Pathology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Kristen W Lynch

    Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    For correspondence
    klync@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0120-8079

Funding

National Institutes of Health (R35 GM118048)

  • Matthew G Thompson
  • Michael J Mallory
  • Max B Ferretti
  • Kristen W Lynch

National Institutes of Health (R01 AI125524)

  • Matthew G Thompson
  • Prasanna Bhat
  • Beatriz MA Fontoura
  • Kristen W Lynch

National Institutes of Health (R01 AI150246,R01 AI122749,R01 AI140539)

  • Mark Dittmar
  • Sara Cherry

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Thompson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,700
    views
  • 458
    downloads
  • 53
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Matthew G Thompson
  2. Mark Dittmar
  3. Michael J Mallory
  4. Prasanna Bhat
  5. Max B Ferretti
  6. Beatriz MA Fontoura
  7. Sara Cherry
  8. Kristen W Lynch
(2020)
Viral-induced alternative splicing of host genes promotes influenza replication
eLife 9:e55500.
https://doi.org/10.7554/eLife.55500

Share this article

https://doi.org/10.7554/eLife.55500

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression

    Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

    Carmina Lichauco, Eric J Foss ... Antonio Bedalov
    Research Article

    The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.

    1. Chromosomes and Gene Expression

    Cryogenic Electron Microscopy: MagIC beads for scarce macromolecules

    Carlos Moreno-Yruela, Beat Fierz
    Insight

    Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.

    1. Chromosomes and Gene Expression
    2. Structural Biology and Molecular Biophysics

    Surprising features of nuclear receptor interaction networks revealed by live-cell single-molecule imaging

    Liza Dahal, Thomas GW Graham ... Xavier Darzacq
    Research Article

    Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.