Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines.
Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines.
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淋巴母细胞系中 Epstein-Barr 病毒核抗原 3C 调节基因。
DOI：
10.1073/pnas.1017419108
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发表时间：
2011
影响因子：
11.1
通讯作者：
Kieff,Elliott
中科院分区：
文献类型：
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作者：
Zhao,Bo;Mar,JessicaC;Maruo,Seiji;Lee,Sungwook;Gewurz,BenjaminE;Johannsen,Eric;Holton,Kristina;Rubio,Renee;Takada,Kenzo;Quackenbush,John;Kieff,Elliott
EB病毒核抗原3C（EBNA3C）是EB病毒转化淋巴母细胞系（LCL）生长所必需的转录因子。为了鉴定LCL中的EBNA3C调节基因，使用微阵列测量条件性表达与4-OH-他莫昔芬依赖性雌激素受体激素结合结构域（EBNA3CHT）融合的EBNA3C的三种不同LCL中的每一种中的RNA丰度。在非允许条件下、允许条件下和具有野生型EBNA3C反式互补的非允许条件下，对每个EBNA3CHT LCL测定至少三种RNA。使用EBNA3C水平的双向ANOVA模型，我们鉴定了550个调节基因，其上调或下调至少1.5倍，错误发现率<0.01。EBNA3C调控的基因与EBNA2和EBNA3A调控的基因显著重叠，这与对细胞基因转录的协同作用一致。在550个EBNA3C调控的基因中，有106个可以被放置在蛋白质网络中。对80个最重要的EBNA3C调控基因的种子贝叶斯网络分析表明，RAC 1、林恩和TNF是其他EBNA3C调控基因的上游。基因集富集分析发现富集MAP激酶信号传导、丝氨酸-细胞因子受体相互作用、JAK-STAT信号传导和细胞粘附分子，暗示这些途径在EBNA3C对LCL生长或存活的影响中。EBNA3C显著上调CXCL12配体及其CXCR4受体，并增加LCL迁移。CXCL12的上调依赖于EBNA3C与细胞转录因子RBPJ的相互作用，RBPJ是LCL生长所必需的。EBNA3C还上调MYC 1.3倍，下调CDKN2A外显子2和3，p16和p14共有1.4倍，错误发现率<5 × 10 − 4。
EBV nuclear antigen 3C (EBNA3C) is an essential transcription factor for EBV transformed lymphoblast cell line (LCL) growth. To identify EBNA3C-regulated genes in LCLs, microarrays were used to measure RNA abundances in each of three different LCLs that conditionally express EBNA3C fused to a 4-OH-Tamoxifen–dependent estrogen receptor hormone binding domain (EBNA3CHT). At least three RNAs were assayed for each EBNA3CHT LCL under nonpermissive conditions, permissive conditions, and nonpermissive conditions with wild-type EBNA3C transcomplementation. Using a two-way ANOVA model of EBNA3C levels, we identified 550 regulated genes that were at least 1.5-fold up- or down-regulated with false discovery rates < 0.01. EBNA3C-regulated genes overlapped significantly with genes regulated by EBNA2 and EBNA3A consistent with coordinated effects on cell gene transcription. Of the 550 EBNA3C-regulated genes, 106 could be placed in protein networks. A seeded Bayesian network analysis of the 80 most significant EBNA3C-regulated genes suggests that RAC1, LYN, and TNF are upstream of other EBNA3C-regulated genes. Gene set enrichment analysis found enrichment for MAP kinase signaling, cytokine–cytokine receptor interactions, JAK-STAT signaling, and cell adhesion molecules, implicating these pathways in EBNA3C effects on LCL growth or survival. EBNA3C significantly up-regulated the CXCL12 ligand and its CXCR4 receptor and increased LCL migration. CXCL12 up-regulation depended on EBNA3C's interaction with the cell transcription factor, RBPJ, which is essential for LCL growth. EBNA3C also up-regulated MYC 1.3-fold and down-regulated CDKN2A exons 2 and 3, shared by p16 and p14, 1.4-fold, with false discovery rates < 5 × 10−4.