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Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation

Yuchen Zhang, Chang Jiang, Stephen J. Trudeau, View ORCID ProfileYohei Narita, Bo Zhao, View ORCID ProfileMingxiang Teng, Rui Guo, Benjamin E Gewurz
doi: https://doi.org/10.1101/2020.04.28.067371
Yuchen Zhang
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China
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Chang Jiang
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3Department of Microbiology, Harvard Medical School, Boston, MA 02115
4Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
7Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
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Stephen J. Trudeau
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3Department of Microbiology, Harvard Medical School, Boston, MA 02115
4Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Yohei Narita
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Bo Zhao
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Mingxiang Teng
6Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
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Rui Guo
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3Department of Microbiology, Harvard Medical School, Boston, MA 02115
4Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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  • For correspondence: bgewurz@bwh.harvard.edu
Benjamin E Gewurz
1Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3Department of Microbiology, Harvard Medical School, Boston, MA 02115
4Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
5Harvard Graduate Program in Virology, Boston, MA 02115
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  • For correspondence: bgewurz@bwh.harvard.edu
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ABSTRACT

Epstein-Barr virus (EBV) infects 95% of adults worldwide and causes infectious mononucleosis. EBV is associated with endemic Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphomas, nasopharyngeal and gastric carcinomas. In these cancers and in most infected B-cells, EBV maintains a state of latency, where nearly 80 lytic cycle antigens are epigenetically suppressed. To gain insights into host epigenetic factors necessary for EBV latency, we recently performed a human genome-wide CRISPR screen that identified the chromatin assembly factor CAF1 as a putative Burkitt latency maintenance factor. CAF1 loads histones H3 and H4 onto newly synthesized host DNA, though its roles in EBV genome chromatin assembly are uncharacterized. Here, we identified that CAF1 depletion triggered lytic reactivation and transforming virion secretion from Burkitt cells, despite strongly also inducing interferon stimulated genes. CAF1 perturbation diminished occupancy of histones 3.1, 3.3 and repressive H3K9me3 and H3K27me3 marks at multiple viral genome lytic cycle regulatory elements. Suggestive of an early role in establishment of latency, EBV strongly upregulated CAF1 expression in newly infected primary human B-cells prior to the first mitosis, and histone 3.1 and 3.3 were loaded on the EBV genome by this timepoint. Knockout of CAF1 subunit CHAF1B impaired establishment of latency in newly EBV-infected Burkitt cells. A non-redundant latency maintenance role was also identified for the DNA synthesis-independent histone 3.3 loader HIRA. Since EBV latency also requires histone chaperones ATRX and DAXX, EBV coopts multiple host histone pathways to maintain latency, and these are potential targets for lytic induction therapeutic approaches.

IMPORTANCE Epstein-Barr virus (EBV) was discovered as the first human tumor virus in endemic Burkitt lymphoma, the most common childhood cancer in sub-Saharan Africa. In Burkitt lymphoma and in 200,000 EBV-associated cancers per year, epigenetic mechanisms maintain viral latency, where lytic cycle factors are silenced. This property complicated EBV’s discovery and facilitates tumor immunoevasion. DNA methylation and chromatin-based mechanisms contribute to lytic gene silencing. Here, we identify histone chaperones CAF1 and HIRA, which have key roles in host DNA replication-dependent and replication independent pathways, respectively, are each important for EBV latency. EBV strongly upregulates CAF1 in newly infected B-cells, where viral genomes acquire histone 3.1 and 3.3 variants prior to the first mitosis. Since histone chaperones ATRX and DAXX also function in maintenance of EBV latency, our results suggest that EBV coopts multiple histone pathways to reprogram viral genomes and highlights targets for lytic induction therapeutic strategies.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted April 30, 2020.
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Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation
Yuchen Zhang, Chang Jiang, Stephen J. Trudeau, Yohei Narita, Bo Zhao, Mingxiang Teng, Rui Guo, Benjamin E Gewurz
bioRxiv 2020.04.28.067371; doi: https://doi.org/10.1101/2020.04.28.067371
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Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation
Yuchen Zhang, Chang Jiang, Stephen J. Trudeau, Yohei Narita, Bo Zhao, Mingxiang Teng, Rui Guo, Benjamin E Gewurz
bioRxiv 2020.04.28.067371; doi: https://doi.org/10.1101/2020.04.28.067371

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