title: Statin-induced changes in gene expression in EBV-transformed and native B-cells.
abstract: Human lymphoblastoid cell lines (LCLs), generated through Epstein-Barr Virus (EBV) transformation of B-lymphocytes (B-cells), are a commonly used model system for identifying genetic influences on human diseases and on drug responses. We have previously used LCLs to examine the cellular effects of genetic variants that modulate the efficacy of statins, the most prescribed class of cholesterol-lowering drugs used for the prevention and treatment of cardiovascular disease. However, statin-induced gene expression differences observed in LCLs may be influenced by their transformation, and thus differ from those observed in native B-cells. To assess this possibility, we prepared LCLs and purified B-cells from the same donors, and compared mRNA profiles after 24 h incubation with simvastatin (2 µm) or sham buffer. Genes involved in cholesterol metabolism were similarly regulated between the two cell types under both the statin and sham-treated conditions, and the statin-induced changes were significantly correlated. Genes whose expression differed between the native and transformed cells were primarily implicated in cell cycle, apoptosis and alternative splicing. We found that ChIP-seq signals for MYC and EBNA2 (an EBV transcriptional co-activator) were significantly enriched in the promoters of genes up-regulated in the LCLs compared with the B-cells, and could be involved in the regulation of cell cycle and alternative splicing. Taken together, the results support the use of LCLs for the study of statin effects on cholesterol metabolism, but suggest that drug effects on cell cycle, apoptosis and alternative splicing may be affected by EBV transformation. This dataset is now uploaded to GEO at the accession number GSE51444.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bolotin
authors.forename: Angela
authors.initials: A
authors.lastname: Armendariz
authors.forename: Kyungpil
authors.initials: K
authors.lastname: Kim
authors.forename: Seok-Jin
authors.initials: SJ
authors.lastname: Heo
authors.forename: Dario
authors.initials: D
authors.lastname: Boffelli
authors.forename: Kelan
authors.initials: K
authors.lastname: Tantisira
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000821:virology; D002461:Cell Line, Transformed; D016000:Cluster Analysis; D019175:DNA Methylation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055106:Genome-Wide Association Study; D004854:Herpesvirus 4, Human; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000378:metabolism
chemical_list: C402641:EBNA-2 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D014764:Viral Proteins