期刊
NATURE GENETICS
卷 46, 期 1, 页码 39-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2849
关键词
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资金
- Cancer Research Society
- National Research and Development Fund (NKFP) [1A/002/2004, TAMOP-4.2.2A-11/1/KONV-2012-0025]
- Canadian Institutes of Health Research [102684]
- Chercheur Clinicien Senior Award
- RMGA (Reseau Medical de Genetique Apliquee
- Network of Applied Genetic Medicine) fellowship
- Fonds de Recherche du Quebec-Sante
- Cedars
- Canadian Institutes of Health Research
- McGill-Canadian Institutes of Health Research Training Program in Systems Biology
- Hungarian Scientific Research Fund (OTKA) [T-04639]
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.
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