DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas.
Aberrant DNA methylation commonly occurs in cancer cells where it has been implicated in the epigenetic silencing of tumor suppressor genes. Additional roles for DNA methylation, such as transcriptional activation, have been predicted but have yet to be clearly demonstrated. The BCL6 oncogene is implicated in the pathogenesis of germinal center-derived B cell lymphomas. We demonstrate that the intragenic CpG islands within the first intron of the human BCL6 locus were hypermethylated in lymphoma cells that expressed high amounts of BCL6 messenger RNA (mRNA). Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. These data indicate that BCL6 expression is maintained during lymphomagenesis in part through DNA methylation that prevents CTCF-mediated silencing.
Lai
Anne Y
AY
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Fatemi
Mehrnaz
M
Dhasarathy
Archana
A
Malone
Christine
C
Sobol
Steve E
SE
Geigerman
Cissy
C
Jaye
David L
DL
Mav
Deepak
D
Shah
Ruchir
R
Li
Leping
L
Wade
Paul A
PA
D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007438:Introns; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C084103:BCL6 protein, human; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins