Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma [methylation data]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE198332 | GEO | 2023/02/26
REPOSITORIES: GEO
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Project description:Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) transforms rodent fibroblasts and is expressed in most EBV-associated malignancies. LMP1 Transformation Effector Site 2 (TES2)/C-Terminal Activation Region 2 (CTAR2) activates NF-kappaB, p38, JNK, ERK and IRF7 pathways. We have investigated LMP1 TES2 genome-wide RNA effects at 4 time points after LMP1 TES2 expression in HEK 293 cells. Using a False Discovery Rate (FDR) of < 0.001 after correction for multiple hypotheses, LMP1 TES2 caused > 2-fold changes in 1916 mRNAs; 1479 RNAs were up-regulated and 437 down-regulated. In contrast to TNFalpha stimulation, which transiently up-regulates many target genes, LMP1 TES2 maintained most RNA effects through the time course, despite robust and sustained induction of negative feedback regulators, such as IkappaBalpha and A20. LMP1 TES2 regulated RNAs encode many NF-kappaB signaling proteins and secondary interacting proteins. Consequently, many LMP1 TES2-regulated RNAs encode proteins that form an extensive interactome. Gene Set Enrichment Analyses found LMP1 TES2 up-regulated genes to be significantly enriched for Pathways in Cancer, B-and T-cell receptor signaling, and Toll-like receptor signaling. Surprisingly, LMP1 TES2 and IkappaBalpha super-repressor co-expression decreased LMP1 TES2 RNA effects to only 5 RNAs with FDR<0.001 and >2 fold change. Thus, canonical NF-kappaB activation is critical for almost all LMP1 TES2 RNA effects in HEK-293 cells and a more significant therapeutic target than previously appreciated. An LMP1 double point mutant (P204A, Q206A) was used to construct a HEK-293 TET-On LMP1 TES2 cell line. Stable cell clones were selected that carry an inducible system for LMP1 TES2 expression. The Tet-system is composed of three parts: 1) the LMP1 TES2 cDNA cloned into the tetracycline-regulated pJEF vector; 2) a tetracycline suppressor (tTS) that binds Tet-operator sites in the absence of tetracyclines and silences expression; 3) a reverse-tetracycline transactivator fused to the 4-hydroxy tamoxifen (4HT) ligand binding domain (rTTA M2). LMP1 expression was induced by addition of doxycycline (1 ug/ml) and 4HT (100 nM). For simultaneous inducible expression of LMP1 TES2 and an IkBa super-repressor, a stable cell line was derived. A pJEF vector encoding IkBa residues 37-317 was introduced into the inducible LMP1 TES2 cell line. Cell lines were cultured with DMEM (GIBCO) supplemented with 10% tetracycline-free serum (Clontech). LMP1 expression was induced by addition of tetracycline (1 ug/ml). RNA samples were collected from triplicate samples using RNABee (Qiagen) according to the manufacturer’s instructions from 293 cells induced for LMP1 TES2 (and IkBa super-repressor, where indicated) expression at 0, 6, 9, 12 and 24 hours of induction. Cells were in the log-phase of growth. Gene expression profiles were assayed using the Affymetrix HU-133 plus2 GeneChip according to the manufacturer's instructions. Real-time RT-PCR was performed with the Power SYBR Green RNA-to-CT™ 1-Step Kit (Applied Biosystems, Foster City, CA). Fold changes were determined using delta delta Ct method and normalized by GAPDH expression levels. RNA expression data were normalized using RMA and array quality assessed by NUSE and RLE scores. The data was collected according to methods that fall under the MIAME standards.
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