Modulation of cellular CpG DNA methylation by Kaposi's sarcoma-associated herpesvirus

Guy Journo, Carmel Tushinsky, Asia Shterngas, Nir Avital, Yonatan Eran, Marcela Viviana Karpuj, Milana Frenkel-Morgenstern, Meir Shamay

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23 Scopus citations

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) is a gammaherpesvirus associated with several human malignancies. DNA methylation at CpG dinucleotides is an epigenetic mark dysregulated in many cancer types and in KSHVinfected cells. Several previous studies have analyzed in detail the CpG methylation of the KSHV episomal genomes, but little is known about the impact of KSHV on the human genome. Our knowledge of cellular CpG methylation in the context of KSHV infection is currently limited to four hypermethylated human gene promoters. Therefore, we undertook a comprehensive CpG methylation analysis of the human methylome in KSHV-infected cells and KSHV-associated primary effusion lymphoma (PEL). We performed Infinium HumanMethylation450K and MethylationEpic BeadChip arrays and identified panels of hyper- and hypomethylated cellular promoters in KSHVinfected cells. We combined our genome-wide methylation analysis with highthroughput RNA sequencing (RNA-seq) to add functional outcomes to the virally induced methylation changes. We were able to correlate many downregulated genes with promoter hypermethylation and upregulated genes with hypomethylation. In addition, we show that treating the cells with a demethylating agent leads to reexpression of these downregulated genes, indicating that, indeed, DNA methylation plays a role in the repression of these human genes. Comparison between de novo infection and PEL suggests that the virus induces initial hypermethylation followed by a slow increase in genome-wide hypomethylation. This study extends our understanding of the relationship between epigenetic changes induced by KSHV infection and tumorigenesis.

Original languageEnglish
Article numbere00008-18
JournalJournal of Virology
Volume92
Issue number16
DOIs
StatePublished - 15 Aug 2018

Bibliographical note

Publisher Copyright:
© 2018 American Society for Microbiology.

Funding

We thank Liat Linde and Nili Avidan for help in the analysis of the 450K and Epic BeadChip results, Jeffrey Vieira for providing the Vero-rKSHV.219 cells, Richard F. Ambinder and S. Diane Hayward for reagents, and S. Diane Hayward for critically reading the manuscript. We are grateful for the support of the Elias, Genevieve and Georgianna Atol Charitable Trust to the Daniella Lee Casper Laboratory in Viral Oncology. This work was supported by grants from the Israel Science Foundation (https://www.isf.org.il) to M.S. (1134/16) and a Research Career Development Award from the Israel Cancer Research Fund (https://www.icrfonline.org/) to M.S. (01282). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

FundersFunder number
Israel Cancer Research Fund
Israel Science Foundation

    Keywords

    • DNA methylation
    • Human herpesviruses
    • Kaposi's sarcoma-associated herpesvirus
    • Primary effusion lymphoma
    • Transcriptional repression

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