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

By Yuchen Zhang, Chang Jiang, Stephen J. Trudeau, Yohei Narita, Bo Zhao, Mingxiang Teng, Rui Guo, Benjamin Gewurz

Posted 30 Apr 2020
bioRxiv DOI: 10.1101/2020.04.28.067371 (published DOI: 10.1128/mBio.01063-20)

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.

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