1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
Nat Genet. 2014 Jan;46(1):39-44. doi: 10.1038/ng.2849. Epub 2013 Dec 8.
Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. 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 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. 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.
具有多层玫瑰花结的胚胎性肿瘤 (ETMRs) 是罕见的致命性小儿脑肿瘤，其特征是 microRNA 簇 C19MC 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，在所有情况下均发现 C19MC 与 TTYH1 融合，从而驱动 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明显不同的特定 DNA 甲基化模式。我们检测到一种以前未表征的 DNMT3B 异构体的极度过表达，该异构体起源于仅在神经管发育的最初几周内活跃的替代启动子。转录和免疫组织化学分析表明，C19MC 依赖性 DNMT3B 失调是由 RBL2 介导的，RBL2 是 DNMT3B 的已知抑制剂。在培养细胞中转染单个 C19MC microRNA 导致 DNMT3B 上调和 RBL2 下调。我们的数据表明，通过胚胎特异性、脑特异性 DNMT3B 异构体介导的表观遗传改变，ETMR 中可能存在早期发育程序的潜在致癌再激活。
