Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells

ABSTRACT Epigenetic modifications play a pivotal role in the expression of the genes of Epstein-Barr virus (EBV). We found that de novo EBV infection of primary B cells caused moderate induction of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase. To investi...

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Autores principales:	Takaya Ichikawa, Yusuke Okuno, Yoshitaka Sato, Fumi Goshima, Hironori Yoshiyama, Teru Kanda, Hiroshi Kimura, Takayuki Murata
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	EBV EZH2 histone methylation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/26a55b52c00c490fbc4d329b80d1d6b7
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spelling	oai:doaj.org-article:26a55b52c00c490fbc4d329b80d1d6b72021-11-15T15:22:21ZRegulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells10.1128/mSphere.00478-182379-5042https://doaj.org/article/26a55b52c00c490fbc4d329b80d1d6b72018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00478-18https://doaj.org/toc/2379-5042ABSTRACT Epigenetic modifications play a pivotal role in the expression of the genes of Epstein-Barr virus (EBV). We found that de novo EBV infection of primary B cells caused moderate induction of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase. To investigate the role of EZH2, we knocked out the EZH2 gene in EBV-negative Akata cells by the CRISPR/Cas9 system and infected the cells with EBV, followed by selection of EBV-positive cells. During the latent state, growth of EZH2-knockout (KO) cells was significantly slower after infection compared to wild-type controls, despite similar levels of viral gene expression between cell lines. After induction of the lytic cycle by anti-IgG, KO of EZH2 caused notable induction of expression of both latent and lytic viral genes, as well as increases in both viral DNA replication and progeny production. These results demonstrate that EZH2 is crucial for the intricate epigenetic regulation of not only lytic but also latent gene expression in Akata cells. IMPORTANCE The life cycle of EBV is regulated by epigenetic modifications, such as CpG methylation and histone modifications. Here, we found that the expression of EZH2, which encodes a histone H3K27 methyltransferase, was induced by EBV infection; therefore, we generated EZH2-KO cells to investigate the role of EZH2 in EBV-infected Akata B cells. Disruption of EZH2 resulted in increased expression of EBV genes during the lytic phase and, therefore, efficient viral replication and progeny production. Our results shed light on the mechanisms underlying reactivation from an epigenetic point of view and further suggest a role for EZH2 as a form of innate immunity that restricts viral replication in infected cells.Takaya IchikawaYusuke OkunoYoshitaka SatoFumi GoshimaHironori YoshiyamaTeru KandaHiroshi KimuraTakayuki MurataAmerican Society for MicrobiologyarticleEBVEZH2histone methylationMicrobiologyQR1-502ENmSphere, Vol 3, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	EBV EZH2 histone methylation Microbiology QR1-502
spellingShingle	EBV EZH2 histone methylation Microbiology QR1-502 Takaya Ichikawa Yusuke Okuno Yoshitaka Sato Fumi Goshima Hironori Yoshiyama Teru Kanda Hiroshi Kimura Takayuki Murata Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells
description	ABSTRACT Epigenetic modifications play a pivotal role in the expression of the genes of Epstein-Barr virus (EBV). We found that de novo EBV infection of primary B cells caused moderate induction of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase. To investigate the role of EZH2, we knocked out the EZH2 gene in EBV-negative Akata cells by the CRISPR/Cas9 system and infected the cells with EBV, followed by selection of EBV-positive cells. During the latent state, growth of EZH2-knockout (KO) cells was significantly slower after infection compared to wild-type controls, despite similar levels of viral gene expression between cell lines. After induction of the lytic cycle by anti-IgG, KO of EZH2 caused notable induction of expression of both latent and lytic viral genes, as well as increases in both viral DNA replication and progeny production. These results demonstrate that EZH2 is crucial for the intricate epigenetic regulation of not only lytic but also latent gene expression in Akata cells. IMPORTANCE The life cycle of EBV is regulated by epigenetic modifications, such as CpG methylation and histone modifications. Here, we found that the expression of EZH2, which encodes a histone H3K27 methyltransferase, was induced by EBV infection; therefore, we generated EZH2-KO cells to investigate the role of EZH2 in EBV-infected Akata B cells. Disruption of EZH2 resulted in increased expression of EBV genes during the lytic phase and, therefore, efficient viral replication and progeny production. Our results shed light on the mechanisms underlying reactivation from an epigenetic point of view and further suggest a role for EZH2 as a form of innate immunity that restricts viral replication in infected cells.
format	article
author	Takaya Ichikawa Yusuke Okuno Yoshitaka Sato Fumi Goshima Hironori Yoshiyama Teru Kanda Hiroshi Kimura Takayuki Murata
author_facet	Takaya Ichikawa Yusuke Okuno Yoshitaka Sato Fumi Goshima Hironori Yoshiyama Teru Kanda Hiroshi Kimura Takayuki Murata
author_sort	Takaya Ichikawa
title	Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells
title_short	Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells
title_full	Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells
title_fullStr	Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells
title_full_unstemmed	Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells
title_sort	regulation of epstein-barr virus life cycle and cell proliferation by histone h3k27 methyltransferase ezh2 in akata cells
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/26a55b52c00c490fbc4d329b80d1d6b7
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Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells

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