title: The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion.
abstract: BACKGROUND
  Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.
  
  
  RESULTS
  We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.
  
  
  CONCLUSIONS
  Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.
authors: Henar
authors: H
authors: Hernando
authors: Claire
authors: C
authors: Shannon-Lowe
authors: Abul B
authors: AB
authors: Islam
authors: Fatima
authors: F
authors: Al-Shahrour
authors: Javier
authors: J
authors: Rodríguez-Ubreva
authors: Virginia C
authors: VC
authors: Rodríguez-Cortez
authors: Biola M
authors: BM
authors: Javierre
authors: Cristina
authors: C
authors: Mangas
authors: Agustín F
authors: AF
authors: Fernández
authors: Maribel
authors: M
authors: Parra
authors: Henri-Jacques
authors: HJ
authors: Delecluse
authors: Manel
authors: M
authors: Esteller
authors: Eduardo
authors: E
authors: López-Granados
authors: Mario F
authors: MF
authors: Fraga
authors: Nuria
authors: N
authors: López-Bigas
authors: Esteban
authors: E
authors: Ballestar
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D049109:Cell Proliferation; D019175:DNA Methylation; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008213:Lymphocyte Activation; D014158:Transcription, Genetic; D015854:Up-Regulation