EB 病毒调节网络在淋巴母细胞系中的作用。
The Epstein-Barr Virus Regulome in Lymphoblastoid Cells.
机构信息
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cell Host Microbe. 2017 Oct 11;22(4):561-573.e4. doi: 10.1016/j.chom.2017.09.001.
Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation.
EB 病毒（EBV）将 B 细胞转化为持续增殖的淋巴母细胞系（LCL），这是 EBV 相关癌症的实验模型。EBV 核抗原（EBNAs）和 LMP1 是 EBV 转录调节剂，对 LCL 的建立、增殖和存活至关重要。从 LCL 的 3D 基因组组织图谱开始，我们构建了一个包含 1992 个病毒/细胞基因和增强子的综合 EBV 调控组。大约 30%的 LCL 生长所必需的基因与 EBV 增强子有关。EBNA2 位点的缺失显著降低了其靶基因的表达。其他 EBV 超级增强子（ESE）靶标包括 MCL1、IRF4 和 EBF。MYC ESE 与 MYC 的转录起始位点的环化依赖于 EBNAs。删除 MYC ESEs 大大降低了 MYC 的表达和 LCL 的生长。EBNA3A/3C 改变了 CDKN2A/B 的空间组织，以抑制衰老。EZH2 抑制减少了 CDKN2A/B 基因座的环化，并降低了 LCL 的生长。本研究提供了 EBV 驱动细胞转化过程中染色质空间组织的全面视图。
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