BMC Genomics (Mar 2024)

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

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

DOI
https://doi.org/10.1186/s12864-024-10183-8
Journal volume & issue
Vol. 25, no. 1
pp. 1 – 21

Abstract

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Abstract 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.

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