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BZLF1 interacts with the chromatin remodeler INO80 promoting escape from latent infections with Epstein-Barr virus

Marisa Schaeffner, Paulina Mrozek-Gorska, Anne Woellmer, View ORCID ProfileTakanobu Tagawa, Alexander Buschle, View ORCID ProfileNils Krietenstein, Corinna Lieleg, View ORCID ProfilePhilipp Korber, View ORCID ProfileWolfgang Hammerschmidt
doi: https://doi.org/10.1101/317354
Marisa Schaeffner
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health Marchioninistr. 25, D-81377 Munich, Germany
2German Centre for Infection Research (DZIF), Partner site Munich, Germany
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Paulina Mrozek-Gorska
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health Marchioninistr. 25, D-81377 Munich, Germany
2German Centre for Infection Research (DZIF), Partner site Munich, Germany
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Anne Woellmer
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health Marchioninistr. 25, D-81377 Munich, Germany
2German Centre for Infection Research (DZIF), Partner site Munich, Germany
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Takanobu Tagawa
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health Marchioninistr. 25, D-81377 Munich, Germany
2German Centre for Infection Research (DZIF), Partner site Munich, Germany
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Alexander Buschle
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health Marchioninistr. 25, D-81377 Munich, Germany
2German Centre for Infection Research (DZIF), Partner site Munich, Germany
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Nils Krietenstein
3Biomedical Center, Molecular Biology, LMU Munich, 82152 Planegg-Martinsried, Germany
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Corinna Lieleg
3Biomedical Center, Molecular Biology, LMU Munich, 82152 Planegg-Martinsried, Germany
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Philipp Korber
3Biomedical Center, Molecular Biology, LMU Munich, 82152 Planegg-Martinsried, Germany
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  • ORCID record for Philipp Korber
Wolfgang Hammerschmidt
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health Marchioninistr. 25, D-81377 Munich, Germany
2German Centre for Infection Research (DZIF), Partner site Munich, Germany
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  • ORCID record for Wolfgang Hammerschmidt
  • For correspondence: hammerschmidt@helmholtz-muenchen.de
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ABSTRACT

A hallmark of Epstein-Barr virus (EBV) infections is its latent phase, when all viral lytic genes are repressed. Repression results from a high nucleosome occupancy and epigenetic silencing by cellular factors such as the Polycomb repressive complex 2 (PRC2) and DNA methyltransferases that respectively introduce repressive histone marks and DNA methylation. The viral transcription factor BZLF1 acts as molecular switch to induce the transition from the latent to the lytic or productive phase of EBV’s life cycle. It is unknown how BZLF1 can bind to the epigenetically silenced viral DNA and whether it directly reactivates the viral genome through chromatin remodeling. We addressed these fundamental questions and found that BZLF1 binds to nucleosomal DNA motifs both in vivo and in vitro, a property characteristic of bona fide pioneer factors. BZLF1 co-precipitates with cellular chromatin remodeler ATPases, and the knock-down of one of them, INO80, impaired lytic reactivation and virus synthesis. We conclude that BZLF1 reactivates the EBV genome by directly binding to silenced chromatin and recruiting cellular chromatin remodeling enzymes, which implement a permissive state for viral transcription. BZLF1 shares this mode of action with a limited number of cellular pioneer factors, which are instrumental in transcriptional activation, differentiation, and reprogramming in all eukaryotic cells.

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Posted May 08, 2018.
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BZLF1 interacts with the chromatin remodeler INO80 promoting escape from latent infections with Epstein-Barr virus
Marisa Schaeffner, Paulina Mrozek-Gorska, Anne Woellmer, Takanobu Tagawa, Alexander Buschle, Nils Krietenstein, Corinna Lieleg, Philipp Korber, Wolfgang Hammerschmidt
bioRxiv 317354; doi: https://doi.org/10.1101/317354
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BZLF1 interacts with the chromatin remodeler INO80 promoting escape from latent infections with Epstein-Barr virus
Marisa Schaeffner, Paulina Mrozek-Gorska, Anne Woellmer, Takanobu Tagawa, Alexander Buschle, Nils Krietenstein, Corinna Lieleg, Philipp Korber, Wolfgang Hammerschmidt
bioRxiv 317354; doi: https://doi.org/10.1101/317354

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