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

Research output: Contribution to journalArticlepeer-review

17 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 - 1 Aug 2018

Bibliographical note

Publisher Copyright:
© 2018 American Society for Microbiology.

Keywords

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

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