Kleinman, Claudia L. and Gerges, Noha and Papillon-Cavanagh, Simon and Sin-Chan, Patrick and Pramatarova, Albena and Hauser, Peter and Garami, Miklos and Klekner, Almos and Bognar, Laszlo (2013) Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nature Genetics, 46 (1). pp. 39-44. ISSN 1061-4036
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Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR.pdf Restricted to Repository staff only Download (986kB) | Request a copy |
Abstract
Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC1,2. 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 promoter3 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 DNMT3B4,5. 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.
| Item Type: | Article |
|---|---|
| Additional Information: | Teljes szerzőség: Kleinman, Claudia L. és Gerges, Noha és Papillon-Cavanagh, Simon és Sin-Chan, Patrick és Pramatarova, Albena és Quang, Dong-Anh Khuong és Adoue, Véronique és Busche, Stephan és Caron, Maxime és Djambazian, Haig és Bemmo, Amandine és Fontebasso, Adam M. és Spence, Tara és Schwartzentruber, Jeremy és Albrecht, Steffen és Hauser, Peter és Garami, Miklos és Klekner, Almos és Bognar, Laszlo és Montes, Jose-Luis és Staffa, Alfredo és Montpetit, Alexandre és Berube, Pierre és Zakrzewska, Magdalena és Zakrzewski, Krzysztof és Liberski, Pawel P. és Dong, Zhifeng és Siegel, Peter M. és Duchaine, Thomas és Perotti, Christian és Fleming, Adam és Faury, Damien és Remke, Marc és Gallo, Marco és Dirks, Peter és Taylor, Michael D. és Sladek, Robert és Pastinen, Tomi és Chan, Jennifer A. és Huang, Annie és Majewski, Jacek és Jabado, Nada |
| Subjects: | R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia |
| Depositing User: | Dr. Álmos Klekner |
| Date Deposited: | 17 Nov 2014 07:36 |
| Last Modified: | 17 Nov 2014 14:32 |
| URI: | http://real.mtak.hu/id/eprint/15343 |
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