Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR
Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR
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DOI：
10.1038/ng.2849
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发表时间：
2014-01-01
期刊：
影响因子：
30.8
通讯作者：
Jabado, Nada
中科院分区：
文献类型：
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作者：
Kleinman, Claudia L.;Gerges, Noha;Jabado, Nada
具有多层玫瑰花结的胚胎肿瘤 (ETMR) 是一种罕见的致命性儿童脑肿瘤，其特征是 microRNA 簇 C19MC(1,2) 的高水平扩增。我们对 12 个 ETMR 样本进行了综合遗传和表观遗传分析，并在所有情况下鉴定出 C19MC 与 TTYH1 融合驱动 microRNA 的表达。 ETMR 肿瘤、细胞系和异种移植物表现出与其他肿瘤和正常组织不同的特定 DNA 甲基化模式。我们检测到先前未表征的 DNMT3B 亚型的极端过度表达，该亚型源自仅在神经管发育的第一周内活跃的替代启动子 (3)。转录和免疫组织化学分析表明，C19MC 依赖性 DNMT3B 失调是由 RBL2（一种已知的 DNMT3B 阻遏蛋白）介导的(4,5)。用单个 C19MC microRNA 转染导致培养细胞中 DNMT3B 上调和 RBL2 下调。我们的数据表明，通过胚胎、大脑特异性 DNMT3B 同工型介导的表观遗传改变，ETMR 中的早期发育程序可能重新参与致癌性。
Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC(1,2). We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter(3) that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B(4,5). Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.