Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines

Bo Zhao, Jessica C. Mar, Seiji Maruo, Sungwook Lee, Benjamin E. Gewurz, Eric Johannsen, Kristina Holton, Renee Rubio, Kenzo Takada, John Quackenbush, Elliott Kieff

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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, JAKSTAT 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.

Original languageEnglish (US)
Pages (from-to)337-342
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number1
DOIs
StatePublished - Jan 4 2011

    Fingerprint

Keywords

  • Lymphoma
  • Notch

ASJC Scopus subject areas

  • General

Cite this

Zhao, B., Mar, J. C., Maruo, S., Lee, S., Gewurz, B. E., Johannsen, E., Holton, K., Rubio, R., Takada, K., Quackenbush, J., & Kieff, E. (2011). Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines. Proceedings of the National Academy of Sciences of the United States of America, 108(1), 337-342. https://doi.org/10.1073/pnas.1017419108