ATRT-05. USING DROSOPHILA TO EXPLORE THE FUNCTIONAL RELEVANCE OF GENES AFFECTED BY EPIGENETIC ALTERATIONS IN ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT)
ATRT-05. USING DROSOPHILA TO EXPLORE THE FUNCTIONAL RELEVANCE OF GENES AFFECTED BY EPIGENETIC ALTERATIONS IN ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT)
复制标题
ATRT-05 使用果蝇探索非典型畸胎瘤/横纹肌样肿瘤 (AT/RT) 中受表观遗传改变影响的基因的功能相关性
DOI：
10.1093/neuonc/noy059.004
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发表时间：
2018
期刊：
影响因子：
15.9
通讯作者：
Hasselblatt
中科院分区：
文献类型：
--
作者：
Tegeder I;Thiel K;Berlandi J;Johann P;Erkek S;Jeibmann A;Hasselblatt
非典型畸胎瘤/横纹肌样瘤（AT/RT）是发生于幼儿的高度恶性脑肿瘤。大多数AT/RT的特征是单个基因失活，即染色质重塑复合体成员SMARCB1 （INI1/hSNF5）。然而，AT/RTs在表观遗传上是异质的，可以根据基因表达、DNA甲基化谱和增强子景观（H3K27ac）划分为分子亚群。对ChIP-seq数据的生物统计学分析显示，大量基因被预测会受到差异组蛋白修饰的影响，但对这些基因在SMARCB1缺陷的有害影响中的功能作用知之甚少。因此，我们在体内SMARCB1缺乏的果蝇模型中使用shRNA修饰子筛选1083个候选基因的功能相关性。在1083个候选基因中的89个被敲除后，Snr1的胶质特异性敲除引起的致死性表型，SMARCB1的苍蝇同源基因被转移到发育的后期。其中包括CG10348，它是转录调节因子PRDM16的苍蝇同源物。我们发现PRDM16在AT/RT中高表达。在smarcb1缺失的横纹肌样肿瘤细胞中敲低PRDM16导致细胞活力显著降低。这些结果表明，苍蝇模型可以用于AT/RT生物学中功能相关基因的鉴定。由IZKF mnster （Ha3/019/15）支持。
Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant brain tumors arising in young children. The majority of AT/RT is characterized by inactivation of one single gene, the chromatin remodeling complex member SMARCB1 (INI1/hSNF5). However, AT/RTs are epigenetically heterogeneous and can be divided into molecular subgroups based on gene expression, DNA methylation profiles and enhancer landscapes (H3K27ac). Biostatistical analysis of ChIP-seq data resulted in a large set of genes predicted to be affected by differential histone modifications, but little is known on the functional role of these genes in the detrimental effects of SMARCB1 deficiency. We thus explored the functional relevance of 1083 candidate genes using shRNA modifier screens in a Drosophila melanogaster model of SMARCB1 deficiency in vivo. The lethal phenotype caused by glial-specific knockdown of Snr1, the fly orthologue of SMARCB1 was shifted to later stages of development upon additional knockdown of 89 out of 1083 candidate genes. These included CG10348, the fly orthologue of transcriptional regulator PRDM16. We found PRDM16 to be highly expressed in AT/RT. Knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells caused a significant reduction in cell viability. These results demonstrate that fly models can be employed for the identification of functionally relevant genes in the biology of AT/RT. Supported by IZKF Münster (Ha3/019/15).