Doerr Jeanette R, Malone Cindy S, Fike Francesca M, Gordon Melinda S, Soghomonian Shahe V, Thomas Roman K, Tao Qian, Murray Paul G, Diehl Volker, Teitell Michael A, Wall Randolph
Department of Microbiology, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
J Mol Biol. 2005 Jul 22;350(4):631-40. doi: 10.1016/j.jmb.2005.05.032.
Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) and primary effusion lymphoma (PEL) are derived from germinal center (GC) and post-GC B cells, respectively. Neither express many of the B cell genes or surface markers typically expressed by other GC-derived B cell lymphomas or normal B cells. This loss of B cell gene expression is not due to a lack of essential transcription factors, as studies have shown that the ectopic expression of missing transcription factors failed to reactivate endogenous target genes. These results implicate epigenetic mechanisms extinguishing B cell gene expression. Silenced endogenous B cell genes representing a surface receptor, B29 (Igbeta, CD79b), a signaling molecule, TCL1, and a transcription factor, Bob1 (OCA-B, OBF-1), were reactivated by 5-aza-2'-deoxycytidine, indicating that gene silencing in HRS and PEL cells is due to DNA methylation. Genomic bisulfite sequencing corroborated this prediction and revealed three distinct patterns of methylation for the silenced B29 and TCL1 promoters. These distinct patterns consisted of 5' promoter CpG methylation alone, 5' and 3' promoter CpG methylation sparing sites in the central cores, and complete CpG methylation throughout the promoter regions. The silenced Bob1 promoter showed one pattern of dense CpG methylation at essentially all sites. These consistent patterns predict that, although gene silencing in many HRS and PEL cells mimics appropriate gene silencing, in some cases of complete CpG methylation throughout entire promoters both the activation and targeting of methylation is abnormal.
经典型霍奇金淋巴瘤（cHL）和原发性渗出性淋巴瘤（PEL）的霍奇金和里德-施特恩伯格（HRS）细胞分别来源于生发中心（GC）和GC后B细胞。它们均不表达许多其他GC来源的B细胞淋巴瘤或正常B细胞通常表达的B细胞基因或表面标志物。B细胞基因表达的这种缺失并非由于缺乏必需的转录因子，因为研究表明，缺失转录因子的异位表达未能重新激活内源性靶基因。这些结果提示表观遗传机制可使B细胞基因表达沉默。代表表面受体B29（Igbeta，CD79b）、信号分子TCL1和转录因子Bob1（OCA-B，OBF-1）的内源性沉默B细胞基因可被5-氮杂-2'-脱氧胞苷重新激活，这表明HRS和PEL细胞中的基因沉默是由于DNA甲基化所致。基因组亚硫酸氢盐测序证实了这一预测，并揭示了沉默的B29和TCL1启动子的三种不同甲基化模式。这些不同模式包括仅5'启动子CpG甲基化、5'和3'启动子CpG甲基化在中央核心区域保留位点以及整个启动子区域完全的CpG甲基化。沉默的Bob1启动子在基本上所有位点均显示出一种密集的CpG甲基化模式。这些一致的模式预示着，尽管许多HRS和PEL细胞中的基因沉默模拟了适当的基因沉默，但在某些整个启动子完全CpG甲基化的情况下，甲基化的激活和靶向都是异常的。
