ATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress

  1. Joseph M Cabral
  2. Hyung Suk Oh
  3. David M Knipe  Is a corresponding author
  1. Harvard Medical School, United States

Abstract

The mechanisms by which mammalian cells recognize and epigenetically restrict viral DNA are not well defined. We used herpes simplex virus with bioorthogonally labeled genomes to detect host factors recruited to viral DNA shortly after its nuclear entry and found that the cellular IFI16, PML, and ATRX proteins colocalized with viral DNA by 15 min post infection. HSV-1 infection of ATRX-depleted fibroblasts resulted in elevated viral mRNA and accelerated viral DNA accumulation. Despite the early association of ATRX with vDNA, we found that initial viral heterochromatin formation is ATRX-independent. However, viral heterochromatin stability required ATRX from 4-8 h post infection. Inhibition of transcription blocked viral chromatin loss in ATRX-knockout cells; thus, ATRX is uniquely required for heterochromatin maintenance during chromatin stress. These results argue that the initial formation and the subsequent maintenance of viral heterochromatin are separable mechanisms, a concept that likely extrapolates to host cell chromatin and viral latency.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. MATLAB based software developed to generate image analysis data is available for use: doi:10.5061/dryad.95fs76f

The following data sets were generated

Article and author information

Author details

  1. Joseph M Cabral

    Department of Microbiology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4733-6612
  2. Hyung Suk Oh

    Department of Microbiology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1739-0389
  3. David M Knipe

    Department of Microbiology, Harvard Medical School, Boston, United States
    For correspondence
    david_knipe@hms.harvard.edu
    Competing interests
    David M Knipe, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1554-6236

Funding

National Institutes of Health (AI106934)

  • David M Knipe

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

Reviewing Editor

  1. Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States

Version history

  1. Received: July 19, 2018
  2. Accepted: November 20, 2018
  3. Accepted Manuscript published: November 22, 2018 (version 1)
  4. Version of Record published: December 27, 2018 (version 2)

Copyright

© 2018, Cabral 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.

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  1. Joseph M Cabral
  2. Hyung Suk Oh
  3. David M Knipe
(2018)
ATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress
eLife 7:e40228.
https://doi.org/10.7554/eLife.40228

Share this article

https://doi.org/10.7554/eLife.40228

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