EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis.

TitleEZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis.
Publication TypeJournal Article
Year of Publication2010
AuthorsVelichutina I, Shaknovich R, Geng H, Johnson NA, Gascoyne RD, Melnick AM, Elemento O
Date Published2010 Dec 09
KeywordsB-Lymphocytes, Cell Proliferation, Cell Transformation, Neoplastic, DNA-Binding Proteins, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Silencing, Germinal Center, Humans, Lymphoma, Large B-Cell, Diffuse, Polycomb Repressive Complex 2, Promoter Regions, Genetic, Transcription Factors, Tumor Cells, Cultured

EZH2 is the catalytic subunit of the PRC2 Polycomb complex and mediates transcriptional repression through its histone methyltransferase activity. EZH2 is up-regulated in normal germinal center (GC) B cells and is implicated in lymphomagenesis. To explore the transcriptional programs controlled by EZH2, we performed chromatin immunoprecipitation (ChIP-on-chip) in GC cells and found that it binds approximately 1800 promoters, often associated with DNA sequences similar to Droso-phila Polycomb response elements. While EZH2 targets overlapped extensively between GC B cells and embryonic stem cells, we also observed a large GC-specific EZH2 regulatory program. These genes are preferentially histone 3 lysine 27-trimethylated and repressed in GC B cells and include several key cell cycle-related tumor suppressor genes. Accordingly, siRNA-mediated down-regulation of EZH2 in diffuse large B-cell lymphoma (DLBCL) cells resulted in acute cell cycle arrest at the G(1)/S transition and up-regulation of its tumor suppressor target genes. At the DNA level, EZH2-bound promoters are hypomethylated in GC B cells, but many of them are aberrantly hypermethylated in DLBCL, suggesting disruption of normal epigenetic processes in these cells. EZH2 is thus involved in regulating a specific epigenetic program in normal GCs, including silencing of antiproliferative genes, which may contribute to the malignant transformation of GC B cells into DLBCLs.

Alternate JournalBlood
PubMed ID20736451
PubMed Central IDPMC3012542
Grant ListK08 CA127353 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
R01 CA104538 / CA / NCI NIH HHS / United States