Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
BMC Genomics. 2024 Mar 12;25(1):273. doi: 10.1186/s12864-024-10183-8.
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.
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.
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.
Epstein-Barr 病毒（EBV）有两种主要的遗传类型：1 型（EBV-1）和 2 型（EBV-2）。EBV 通过操纵宿主 B 细胞中的基因表达来发挥作用，使用病毒编码的基因调节蛋白，包括 Epstein-Barr 核抗原 2（EBNA2）。虽然 1 型 EBNA2 已知与人类转录因子（hTFs）如 RBPJ、EBF1 和 SPI1（PU.1）相互作用，但 2 型 EBNA2 与 1 型的氨基酸同一性仅约为 50%，因此可能具有不同的结合伙伴、人类基因组结合位置和功能。
在这项研究中，我们检查了 EBV-1 和 EBV-2 转化的人类 B 细胞中的全基因组 EBNA2 结合，以鉴定与人类基因组共享和独特的 EBNA2 相互作用，揭示了数千个特定类型的 EBNA2 ChIP-seq 峰。基于 hTF 基序的计算预测和随后的 ChIP-seq 实验表明，1 型和 2 型 EBNA2 都与 SPI1 和 AP-1（BATF 和 JUNB）hTF 共同占据基因组。然而，1 型 EBNA2 显示与 EBF1 优先共占据，而 2 型 EBNA2 优先与 RBPJ 共占据。这些 hTF 共占据的差异揭示了已知的 EBNA2 人类靶基因的特定类型基因表达的可能机制：MYC（共享）、CXCR7（1 型特异性）和 CD21（2 型特异性）。1 型和 2 型 EBNA2 结合事件均在系统性红斑狼疮（SLE）和多发性硬化症（MS）风险基因座中富集，而原发性胆汁性胆管炎（PBC）风险基因座则特异性富集 2 型峰。
这项研究揭示了广泛的特定类型的 EBNA2 与人类基因组的相互作用、EBNA2 相互作用伙伴的可能差异，以及 2 型 EBNA2 在自身免疫性疾病中的新作用。我们的研究结果强调了在人类基因表达和疾病相关研究中考虑 EBV 类型的重要性。
