DNA methylation dominates transcriptional silencing of Pax5 in terminally differentiated B cell lines
DNA methylation dominates transcriptional silencing of Pax5 in terminally differentiated B cell lines
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DOI：
10.1016/s0161-5890(02)00003-2
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发表时间：
2002-06-01
影响因子：
3.6
通讯作者：
Takagaki, Y
中科院分区：
文献类型：
--
作者：
Danbara, M;Kameyama, K;Takagaki, Y
Pax 5在B细胞发育过程中起着关键作用，其表达范围广泛，从早期谱系定型前体细胞到成熟B细胞。但在终末分化的浆细胞中沉默。在这份报告中，我们表明DNA甲基化参与了Pax 5的沉默。在表达Pax 5的细胞系38139（前B）和2 PK-3（成熟B）中，含TATA的上游启动子中的所有CpG位点都未甲基化，而这些位点在不表达Pax 5的骨髓瘤细胞系FO和Sp-2/0中完全甲基化。用5-氮杂-2 '-脱氧胞苷（5-aza-dC）使FO和Sp-2/0去甲基化导致Pax 5再表达，同时伴随着CD 19和mb-1基因的表达，这些基因已知是Pax 5的靶基因。组蛋白去乙酰化酶的特异性抑制剂甲磺酸（TSA）也能诱导Pax 5的再表达。这种重新表达是。然而，仅从TATA较少的下游启动子转录。带去乙醚。我们的结论是，上游启动子主要被DNA甲基化失活，而下游启动子则被历史性的去乙酰化抑制。两种启动子的协同失活导致终末分化的B细胞系中Pax 5表达的最终沉默。(C)2002年由Elsevier Science Ltd.出版
Pax5 plays a key role in the progression of B cell development, Its expression is observed in a wide range of cell types from early lineage-committed precursors up to mature B cells. but is silenced in terminal differentiated plasma cells. In this report, we show that DNA methylation is involved in the silencing of Pax5. In the Pax5-expressing cell lines 38139 (pre-B) and 2PK-3 (mature B), all CpG sites in TATA-containing upstream promoter were unmethylated, whereas these sites were completely methylated in myeloma cell lines FO and Sp-2/0, which do not express Pax5. Demethylation of FO and Sp-2/0 with 5-aza-2'-deoxycytidine (5-aza-dC) resulted in Pax5 re-expression with the concomitant expression of CD19 and mb-1 genes, which are known to be the target genes of Pax5. Re-expression of Pax5 was also induced by trichostatin A (TSA), which was a specific inhibitor of histone deacetylase. This re-expression was. however, transcribed only from the TATA-less downstream promoter. Taken to-ether. we concluded that the upstream promoter was predominantly inactivated by DNA methylation, while the downstream promoter was repressed by the historic deacetylation. This synergetic inactivation of two promoters results in the final silencing of Pax5 expression in terminally differentiated B cell lines. (C) 2002 Published by Elsevier Science Ltd.