Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Blood. 2010 Dec 9;116(24):5247-55. doi: 10.1182/blood-2010-04-280149. Epub 2010 Aug 24.
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.
EZH2 是 PRC2 多梳复合物的催化亚基，通过其组蛋白甲基转移酶活性介导转录抑制。EZH2 在正常生发中心（GC）B 细胞中上调，并与淋巴瘤发生有关。为了探索 EZH2 控制的转录程序，我们在 GC 细胞中进行了染色质免疫沉淀（ChIP-on-chip），发现它结合了大约 1800 个启动子，通常与类似于果蝇多梳反应元件的 DNA 序列相关。虽然 EZH2 在 GC B 细胞和胚胎干细胞之间的靶标重叠广泛，但我们也观察到一个大型 GC 特异性 EZH2 调控程序。这些基因在 GC B 细胞中优先被组蛋白 3 赖氨酸 27 三甲基化并受到抑制，并且包括几个关键的细胞周期相关肿瘤抑制基因。相应地，siRNA 介导的弥漫性大 B 细胞淋巴瘤（DLBCL）细胞中 EZH2 的下调导致 G1/S 期的急性细胞周期停滞，并上调其肿瘤抑制靶基因。在 DNA 水平上，GC B 细胞中 EZH2 结合的启动子呈低甲基化，但在 DLBCL 中许多启动子呈异常高甲基化，表明这些细胞中正常表观遗传过程被破坏。EZH2 因此参与调节正常 GC 中的特定表观遗传程序，包括抑制增殖基因，这可能有助于 GC B 细胞向 DLBCL 的恶性转化。
