Molecular network of chromatin immunoprecipitation followed by deep sequencing-based (ChIP-Seq) Epstein-Barr virus nuclear antigen 1-target cellular genes supports biological implications of Epstein-Barr virus persistence in multiple sclerosis

Abstract

Objectives Epstein–Barr virus (EBV) infection confers a strong risk factor for development of multiple sclerosis (MS). EBV preferentially infects B lymphocytes to establish a life-long latent infection. EBV nuclear antigen 1 (EBNA1), acting as a transcriptional activator, plays a central role in the replication and maintenance of the latent episomal EBV genome in EBV-infected host cells. However, the comprehensive set of host cellular genes directly regulated by EBNA1 relevant to the immunopathogenesis of MS remains to be elucidated. Methods We investigated the chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset of Raji cells, an EBV-positive Burkitt's lymphoma cell line. We studied the molecular network of target genes by pathway analysis tools of bioinformatics. Results We identified the set of 228 EBNA1-target cellular genes. The EBNA1-binding sites were located mainly in intronic regions of target genes with an existence of the palindromic consensus sequence motif. By pathway analysis using Ingenuity Pathways Analysis and KeyMolnet, the EBNA1-target cellular gene network showed a significant relationship with the networks related to cell death and survival, and transcriptional regulation by interferon-regulatory factor (IRF), and signal transducer and activator of transcription (STAT). Conclusions These results show that the EBNA1-target cellular gene network is closely associated with maintenance of EBV persistence by controlling the fate of EBV-infected host cells, and by aberrantly regulating the production of host-derived antiviral interferons and other cytokines, supporting biological implications of EBV persistence in MS.