ATRT-09. CHROMATIN SEGMENTATION ANALYSES IN ATYPICAL TERATOID/RHABDOID TUMORS REVEAL H3K27ME3-MEDIATED EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES AND IDENTIFY A NOVEL ROLE OF EZH2, ASSOCIATED WITH ACTIVE CHROMATIN

Abstract

AbstractAlthough SMARCB1 mutations represent the only genetic aberrations in atypical teratoid / rhabdoid tumors (ATRT), a comprehensive assessment of the epigenetic effect of SMARCB1 loss has not been achieved so far. We performed ChIP-sequencing for six active and repressive histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac, H3K9me3, H3K36me3) and EZH2 in 11 primary ATRTs, encompassing all three molecular subgroups of ATRT. Chromatin segmentation analyses revealed that across all three subgroups a high percentage of ATRT genomes resides in a quiescent state and active enhancer states are significantly underrepresented as compared to non-neoplastic brain tissues. These data show that loss of SMARCB1 generally results in a subgroup independent repression of genes In addition, we observed gain of the repressive mark H3K27me3 in ATRTs at genes bound by SMARCB1 in normal brain, in line with the known antagonistic role between SMARCB1 and EZH2. Tumor suppressor genes and neuronal transcription factors (such as NEUROD2) were particularly affected by this mechanism of epigenetic silencing. Interestingly, by comparing the genome wide distribution of EZH2 and H3K27me3, we also identified classes of ATRT-specific active genes bound by EZH2, but lackingH3K27me3, pointing at a non-canonical role of EZH2 in gene activation. In subgroup ATRT-TYR, which displayed the most striking pattern of EZH2 associated gene activation, this pattern could for instance explain the overexpression of previously identified subgroup specific signature genes such as BMP4. The comprehensive study of histone marks in this genomically simple but epigenetically heterogeneous disease enabled us to not only shed 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.