Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors
Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors
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预测受非典型畸胎瘤/横纹肌样肿瘤表观遗传改变影响的基因的功能相关性
DOI：
10.1007/s11060-018-03018-6
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发表时间：
2019
影响因子：
3.9
通讯作者：
Martin
中科院分区：
文献类型：
--
作者：
Tegeder;Isabel;Katharina;Johann;Pascal D;Berlandi;Johannes;Thatikonda;Frühwald;Michael C;Marcel;Jeibmann;Astrid;Hasselblatt;Martin
目的非典型畸胎样/横纹肌样肿瘤（ATRT）是一种高度恶性的脑肿瘤，好发于婴儿。SWI/SNF染色质重塑复合物成员SMARCB 1/INI 1或（罕见）SMARCA 4/Brg 1的突变是唯一的复发性遗传病变。表观遗传学研究揭示了大量的基因预测受到ATRT中的差异组蛋白修饰的影响，但这些基因在ATRT生物学中的作用仍然不确定。因此，我们的目的是探索这些基因的SMARCB 1缺陷的有害影响的作用。MethodsThe功能相关的1083个基因预测受到影响的表观遗传学改变ATRT在体内使用aDrosophila melanogastermodel的SMARCB 1缺陷。人类直系同源基因的敲除修改的表型在Gal 4-UAS飞模型中进一步检查ATRT样品和SMARCB 1缺陷横纹肌样瘤cells.ResultsKnockdown的Snr 1，飞直系同源SMARCB 1，导致在一个致命的表型和表观遗传学的改变飞模型。在体内筛选的1083个基因中的89个基因的额外siRNA敲低后，致死表型转移到发育的后期阶段。这些包括TGF-β受体信号通路相关基因，例如CG 10348，转录调节因子PRDM 16的果蝇直向同源物。随后，PRDM 16被发现是过度表达的ATRT样品和敲低的PRDM 16 SMARCB 1缺陷横纹肌样肿瘤细胞减少proliferation.ConclusionsThese结果表明，一个子集的基因受差异组蛋白修饰ATRT是参与SMARCB 1缺陷的不利影响，也相关的ATRT的生物学。
PurposeAtypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.MethodsThe functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using aDrosophila melanogastermodel of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.ResultsKnockdown ofSnr1, the fly orthologue ofSMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g.CG10348, the fly orthologue of transcriptional regulatorPRDM16. Subsequently,PRDM16was found to be over-expressed in ATRT samples and knockdown ofPRDM16in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.ConclusionsThese results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT.
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影响因子：
15.9
作者：
Birks, Diane K.;Donson, Andrew M.;Foreman, Nicholas K.
通讯作者：
Foreman, Nicholas K.
影响因子：
29
作者：
Seale, Patrick;Kajimura, Shingo;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
11.2
作者：
J. Biegel;Jun Zhou;L. Rorke;C. Stenstrom;L. Wainwright;Benjamin Fogelgren
通讯作者：
J. Biegel;Jun Zhou;L. Rorke;C. Stenstrom;L. Wainwright;Benjamin Fogelgren
影响因子：
50.3
作者：
Johann, Pascal D.;Erkek, Serap;Kool, Marcel
通讯作者：
Kool, Marcel
影响因子：
14.9
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.