GENT-28. THE EPIGENETIC LANDSCAPE OF ATYPICAL TERATOID/ RHABDOID TUMORS REVEALS A REPRESSED METHYLOME AND EPIGENETIC SWITCHES AT SMARCB1 BINDING SITESстатья из журнала
Аннотация: Even though SMARCB1 mutations are the only genetic aberrations in atypical teratoid / rhabdoid tumors (ATRT), we recently demonstrated that distinct molecular subgroups exist. However, the broad effects of SMARCB1loss on the epigenetic landscape of these three subgroups remain unclear. We performed ChIPsequencing for six active and repressive histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac, H3K9me3, H3K36me3) and EZH2 in 11 primary AT/RT, encompassing all three subgroups. DNA-methylation and gene expression data were available for all cases and integrated into the analysis. The overall chromatin analysis, compared to non-neoplastic brain tissues, revealed that for all three subgroups a high percentage of the AT/RT genome is either in a quiescent or polycomb repressed state and a significantly lower percentage of the AT/RT genome is in an active enhancer state, suggesting a subgroup independent effect of SMARCB1loss in these tumors. There is, however, a clear difference between the subgroups regarding the distribution of specific enhancer and repressive marks. Surprisingly, we discovered a dual role of EZH2, not only associated with repressed chromatin, but also with active promoters. SMARCB1 ChIP-seq analyses in normal brain suggested that in AT/RT a transition from active chromatin states to either bivalent or repressed chromatin states at SMARCB1 binding sites takes place. Due to this switch at SMARCB1 binding sites, we detected several tumor suppressors transcriptionally repressed. These may play a role in AT/RT tumorigenesis. Our comprehensive study of histone marks in this gentically homogeneous but epigenetically heterogeneous disease enabled us to not only shed a light on the chromatin landscape of these tumors but also on the potentially tumorigenic consequences of SMARCB1 loss. In addition, the dual role of EZH2 in these tumors further enhances the importance of this molecule as a therapeutic target and underlines the importance of clinically targeting this molecule.
Год издания: 2016
Авторы: Serap Erkek, Pascal D. Johann, Kornelius Kerl, Martina Finetti, Marc Zapatka, Michael Fruehwald, Lukas Chávez, Amar Gajjar, Daniel Williamson, Martin Hasselblatt, Stefan M. Pfister, Marcel Kool
Издательство: Oxford University Press
Источник: Neuro-Oncology
Ключевые слова: Chromatin Remodeling and Cancer
Открытый доступ: closed
Том: 18
Выпуск: suppl_6
Страницы: vi80–vi80