Interplay between the Epigenetic Enzyme Lysine (K)-Specific Demethylase 2B and Epstein-Barr Virus Infection

• Published in: Journal of virology Vol. 93; no. 13
• Main Authors: Vargas-Ayala, Romina C, Jay, Antonin, Manara, Francesca, Maroui, Mohamed Ali, Hernandez-Vargas, Hector, Diederichs, Audrey, Robitaille, Alexis, Sirand, Cecilia, Ceraolo, Maria Grazia, Romero-Medina, Maria Carmen, Cros, Marie Pierre, Cuenin, Cyrille, Durand, Geoffroy, Le Calvez-Kelm, Florence, Mundo, Lucia, Leoncini, Lorenzo, Manet, Evelyne, Herceg, Zdenko, Gruffat, Henri, Accardi, Rosita
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-07-2019
• Subjects: Adolescent; Adult; B-Lymphocytes - virology; Biochemistry, Molecular Biology; Burkitt Lymphoma - metabolism; Cancer; Cell Line; Child; Child, Preschool; Chromatin - metabolism; Chromatin Immunoprecipitation; DNA Methylation; Down-Regulation; Epigenesis, Genetic; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; Female; Gene Expression Regulation; Herpesvirus 4, Human - physiology; Human health and pathology; Humans; Infectious diseases; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Life Sciences; Male; Microbiology and Parasitology; Middle Aged; Molecular biology; Virology; Virus-Cell Interactions; Young Adult; EBV; KDM2B; epigenetic; Burkitt lymphomas
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.00273-19

The histone modifier lysine (K)-specific demethylase 2B (KDM2B) plays a role in the differentiation of hematopoietic cells, and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that the
gene is differentially methylated in cell lines derived from Epstein-Barr virus (EBV)-associated endemic Burkitt lymphoma (eBL) compared with that in EBV-negative sporadic Burkitt lymphoma-derived cells. However, whether KDM2B plays a role in eBL development has not been previously investigated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here, we investigated whether EBV alters KDM2B levels to enable its life cycle and promote B-cell transformation. We show that infection of B cells with EBV leads to downregulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to the
gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV-infected B cells, we show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis.
In Africa, Epstein-Barr virus infection is associated with endemic Burkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared with those leading to sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared with sporadic Burkitt lymphoma cell lines, we identified several differential methylated genomic positions in the proximity of genes with a potential role in cancer, and among them was the
gene.
encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has not been investigated before. In this study, we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We also reveal a role of the demethylase in controlling viral and B-cell gene expression, thus highlighting a novel interaction between the virus and the cellular epigenome.