DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis.
DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis.
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DOI：
10.1158/0008-5472.can-10-0847
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Godley LA
中科院分区：
文献类型：
--
作者：
Shah MY;Vasanthakumar A;Barnes NY;Figueroa ME;Kamp A;Hendrick C;Ostler KR;Davis EM;Lin S;Anastasi J;Le Beau MM;Moskowitz IP;Melnick A;Pytel P;Godley LA
表观遗传变化是在癌细胞中观察到的最常见的改变之一，但癌细胞获得和维持异常DNA甲基化模式的机制尚不清楚。癌细胞具有改变的DNA甲基化分布，并表达异常的DNA甲基转移酶3B转录物，其编码截短的蛋白质，其中一些缺乏C-末端催化结构域。为了测试截短的DNMT 3B同种型是否破坏体内DNA甲基化，我们构建了两个表达DNMT 3B 7的转基因小鼠系，DNMT 3B 7是一种常见于癌细胞中的截短的DNMT 3B同种型。DNMT 3B 7转基因小鼠表现出胚胎发育的改变，包括淋巴细胞减少症、颅面畸形和心脏缺陷，类似于Dnmt 3b缺陷动物，但很少发生癌症。然而，当将DNMT 3B 7转基因小鼠与Eμ-Myc转基因小鼠（其模拟侵袭性B细胞淋巴瘤）交配时，DNMT 3B 7表达增加Eμ-Myc动物中纵隔淋巴瘤的频率。与Eμ-Myc淋巴瘤相比，Eμ-Myc/DNMT 3B 7纵隔淋巴瘤具有更多的染色体重排、增加的总体DNA甲基化水平和更多的基因座特异性DNA甲基化模式扰动。这些数据代表了癌症相关DNA甲基化变化的第一个体内建模，并表明截短的DNMT 3B亚型有助于DNA甲基化的重新分布，几乎表征了每一种人类肿瘤。
Epigenetic changes are among the most common alterations observed in cancer cells, yet the mechanism by which cancer cells acquire and maintain abnormal DNA methylation patterns is not understood. Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins, some of which lack the C-terminal catalytic domain. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed two lines of transgenic mice expressing DNMT3B7, a truncated DNMT3B isoform commonly found in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, when DNMT3B7 transgenic are bred with Eμ-Myc transgenic mice, which model aggressive B cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Eμ-Myc animals. Eμ-Myc/DNMT3B7 mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to Eμ-Myc lymphomas. These data represent the first in vivo modeling of cancer-associated DNA methylation changes and suggest that truncated DNMT3B isoforms contribute to the re-distribution of DNA methylation characterizing virtually every human tumor.