DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation
DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation
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DOI：
10.1182/blood-2011-06-357996
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发表时间：
2011-09-29
期刊：
影响因子：
20.3
通讯作者：
Melnick, Ari
中科院分区：
文献类型：
--
作者：
Shaknovich, Rita;Cerchietti, Leandro;Melnick, Ari
生发中心(Gc)B细胞的表型包括耐受快速增殖的独特能力和激活诱导的胞嘧啶脱氨酶(AICDA)的诱变作用。鉴于表观遗传模式在确定细胞表型中的重要性，我们研究了DNA甲基化和DNA甲基转移酶在GC形成中的作用。DNA甲基化图谱显示，与静息/幼稚B细胞相比，GC B细胞中的DNA甲基化模式发生了显著变化。这一转变包括235个基因的显著差异甲基化，基因表达的一致反向变化最显著地影响了NFkB和MAP激酶信号通路的基因。与未甲基化的B细胞相比，GC B细胞以低甲基化为主，AICDA结合位点在低甲基化的基因座中高度表达。GC B细胞的DNA甲基化异质性也高于未分化B细胞。在DNA甲基转移酶(DNMT)中，只有DNMT1在GC B细胞中显著上调。DNMT1亚型小鼠存在GC形成缺陷，用DNA甲基转移酶抑制剂地西他滨治疗后，小鼠在免疫刺激后不能形成GC。值得注意的是，DNMT1亚型动物的GC B细胞显示出DNA损伤增加的证据，这表明DNMT1在DNA甲基化和双链DNA断裂修复中具有双重作用。(血。2011；118(13)：3559-3569)
The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair. (Blood. 2011;118(13):3559-3569)