September 22, 2019  |  

Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR.

Authors: Kleinman, Claudia L and Gerges, Noha and Papillon-Cavanagh, Simon and Sin-Chan, Patrick and Pramatarova, Albena and Quang, Dong-Anh Khuong and Adoue, Véronique and Busche, Stephan and Caron, Maxime and Djambazian, Haig and Bemmo, Amandine and Fontebasso, Adam M and Spence, Tara and Schwartzentruber, Jeremy and Albrecht, Steffen and Hauser, Peter and Garami, Miklos and Klekner, Almos and Bognar, Laszlo and Montes, Jose-Luis and Staffa, Alfredo and Montpetit, Alexandre and Berube, Pierre and Zakrzewska, Magdalena and Zakrzewski, Krzysztof and Liberski, Pawel P and Dong, Zhifeng and Siegel, Peter M and Duchaine, Thomas and Perotti, Christian and Fleming, Adam and Faury, Damien and Remke, Marc and Gallo, Marco and Dirks, Peter and Taylor, Michael D and Sladek, Robert and Pastinen, Tomi and Chan, Jennifer A and Huang, Annie and Majewski, Jacek and Jabado, Nada

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.

Journal: Nature genetics
DOI: 10.1038/ng.2849
Year: 2014

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