Journal Article

Shared and distinct interactions of type 1 and type 2 Epstein-Barr Nuclear Antigen 2 with the human genome

Diouf, Arame A., Ernst, Kevin, Gewurz, Ben, Guo, Rui, Weirauch, Matthew T., Parameswaran, Sreeja, Yin, Cailing, Hass, Matthew R., Viel, Kenyatta C. M. F., Jones, Sydney H., VonHandorf, Andrew, Rowden, Hope, Dunn, Katelyn A., Edsall, Lee E., Gittens, Olivia E., Chen, Xiaoting, Forney, Carmy R., Zhao, Bo, Kaufman, Kenneth M., Kottyan, Leah C., Donmez, Omer A., Prosser, Hayley K., Lawson, Lucinda P., Leong, Merrin Man Long

2024

Overview

Background There are two major genetic types of Epstein-Barr Virus (EBV): type 1 (EBV-1) and type 2 (EBV-2). EBV functions by manipulating gene expression in host B cells, using virus-encoded gene regulatory proteins including Epstein-Barr Nuclear Antigen 2 (EBNA2). While type 1 EBNA2 is known to interact with human transcription factors (hTFs) such as RBPJ, EBF1, and SPI1 (PU.1), type 2 EBNA2 shares only ~ 50% amino acid identity with type 1 and thus may have distinct binding partners, human genome binding locations, and functions. Results In this study, we examined genome-wide EBNA2 binding in EBV-1 and EBV-2 transformed human B cells to identify shared and unique EBNA2 interactions with the human genome, revealing thousands of type-specific EBNA2 ChIP-seq peaks. Computational predictions based on hTF motifs and subsequent ChIP-seq experiments revealed that both type 1 and 2 EBNA2 co-occupy the genome with SPI1 and AP-1 (BATF and JUNB) hTFs. However, type 1 EBNA2 showed preferential co-occupancy with EBF1, and type 2 EBNA2 preferred RBPJ. These differences in hTF co-occupancy revealed possible mechanisms underlying type-specific gene expression of known EBNA2 human target genes: MYC (shared), CXCR7 (type 1 specific), and CD21 (type 2 specific). Both type 1 and 2 EBNA2 binding events were enriched at systemic lupus erythematosus (SLE) and multiple sclerosis (MS) risk loci, while primary biliary cholangitis (PBC) risk loci were specifically enriched for type 2 peaks. Conclusions This study reveals extensive type-specific EBNA2 interactions with the human genome, possible differences in EBNA2 interaction partners, and a possible new role for type 2 EBNA2 in autoimmune disorders. Our results highlight the importance of considering EBV type in the control of human gene expression and disease-related investigations.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Activator protein 1 / Amino acids / Analysis / Animal Genetics and Genomics / Antigens / Autoimmune diseases / Autoimmune disorders / Binding / Biomedical and Life Sciences / Cells / ChIP-seq / Cholangitis / Chronic conditions / Control / Datasets / Disease / EBNA2 / EBV / Epstein-Barr virus / Epstein-Barr Virus Infections - genetics / Epstein-Barr Virus Infections - metabolism / Epstein-Barr Virus Nuclear Antigens - genetics / Epstein-Barr Virus Nuclear Antigens - metabolism / Functional genomics / Gene expression / Gene regulation / Genome, Human / Genomes / Health risk assessment / Herpesvirus 4, Human - genetics / Herpesvirus 4, Human - metabolism / Humans / Identification and classification / Infections / JunB protein / Kinases / Life Sciences / Lymphocytes B / Lymphoma / Medicine, Preventive / Methods / Microarrays / Microbial Genetics and Genomics / Molecular mechanics / Multiple sclerosis / Myc protein / Plant Genetics and Genomics / Prevention / Preventive health services / Proteins / Proteomics / PU.1 protein / Regulatory proteins / Risk factors / Systemic lupus erythematosus / Transcription factors / Transcription Factors - metabolism / Viral Proteins - genetics / Viruses