Department of Molecular Genetics and Microbiology, Duke Center for Virology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Molecular Genetics and Microbiology, Duke Center for Virology, Duke University School of Medicine, Durham, NC 27710, USA.
Cell Rep. 2023 Aug 29;42(8):112958. doi: 10.1016/j.celrep.2023.112958. Epub 2023 Aug 9.
Chromatin accessibility fundamentally governs gene expression and biological response programs that can be manipulated by pathogens. Here we capture dynamic chromatin landscapes of individual B cells during Epstein-Barr virus (EBV) infection. EBV cells that exhibit arrest via antiviral sensing and proliferation-linked DNA damage experience global accessibility reduction. Proliferative EBV cells develop expression-linked architectures and motif accessibility profiles resembling in vivo germinal center (GC) phenotypes. Remarkably, EBV elicits dark zone (DZ), light zone (LZ), and post-GC B cell chromatin features despite BCL6 downregulation. Integration of single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), single-cell RNA sequencing (scRNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) data enables genome-wide cis-regulatory predictions implicating EBV nuclear antigens (EBNAs) in phenotype-specific control of GC B cell activation, survival, and immune evasion. Knockouts validate bioinformatically identified regulators (MEF2C and NFE2L2) of EBV-induced GC phenotypes and EBNA-associated loci that regulate gene expression (CD274/PD-L1). These data and methods can inform high-resolution investigations of EBV-host interactions, B cell fates, and virus-mediated lymphomagenesis.
染色质可及性从根本上控制着基因表达和生物反应程序，这些程序可被病原体操纵。在这里，我们捕获了个体 B 细胞在 Epstein-Barr 病毒 (EBV) 感染过程中的动态染色质景观。通过抗病毒感应和增殖相关的 DNA 损伤而表现出停滞的 EBV 细胞经历了全局可及性降低。增殖性 EBV 细胞形成的表达相关结构和基序可及性特征类似于体内生发中心 (GC) 表型。值得注意的是，尽管 BCL6 下调，EBV 仍能引发暗区 (DZ)、亮区 (LZ) 和 GC 后 B 细胞染色质特征。单细胞转座酶可及染色质测序 (scATAC-seq)、单细胞 RNA 测序 (scRNA-seq) 和染色质免疫沉淀测序 (ChIP-seq) 数据的单细胞分析，能够进行全基因组顺式调控预测，表明 EBV 核抗原 (EBNAs) 可特异性控制 GC B 细胞的激活、存活和免疫逃逸。敲除实验验证了 EBV 诱导的 GC 表型和 EBNA 相关基因座的生物信息学鉴定调控因子 (MEF2C 和 NFE2L2)，这些基因座可调控基因表达 (CD274/PD-L1)。这些数据和方法可以为 EBV-宿主相互作用、B 细胞命运和病毒介导的淋巴瘤发生的高分辨率研究提供信息。
