Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies.
Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies.
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DOI：
10.1101/gad.315192.118
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发表时间：
2018-08-01
影响因子：
10.5
通讯作者：
Rivera MN
中科院分区：
文献类型：
--
作者：
Boulay G;Volorio A;Iyer S;Broye LC;Stamenkovic I;Riggi N;Rivera MN
Boulay等人发现，微卫星重复序列的一个子集在尤文肉瘤中具有转录活性，沉默单个重复序列会破坏局部新生转录，导致推定靶基因的表达显著降低。各种类型的重复序列在癌症中失调。在尤文肉瘤中，致癌融合蛋白EWS-FLI 1诱导染色质特征典型的GGAA微卫星重复的活性增强子，但这些网站的功能还没有直接证明。在这里，通过将新生转录谱分析与表观基因组编辑相结合，我们发现GGAA微卫星重复序列的一个子集在尤文肉瘤中具有转录活性，并且沉默单个重复序列消除了局部新生转录，并导致推定靶基因的表达显著降低。这些重复位点的表观基因组沉默不影响无关细胞中的基因表达，可以防止EWS-FLI 1诱导基因表达，并且在距离470 kb控制SOX 2表达的GGAA重复的情况下，足以损害尤文肉瘤异种移植物的生长。使用广泛适用于测试不同类型的重复基因组元件的实验方法，我们的研究直接证明了特定的重复微卫星在癌症中具有关键的基因调控功能，因此代表了肿瘤特异性的脆弱性，可用于开发新的疗法。
Boulay et al. find that a subset of microsatellite repeats is transcriptionally active in Ewing sarcoma and that silencing individual repeats abolishes local nascent transcription and leads to markedly reduced expression of putative target genes. Various types of repetitive sequences are dysregulated in cancer. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 induces chromatin features typical of active enhancers at GGAA microsatellite repeats, but the function of these sites has not been directly demonstrated. Here, by combining nascent transcription profiling with epigenome editing, we found that a subset of GGAA microsatellite repeats is transcriptionally active in Ewing sarcoma and that silencing individual repeats abolishes local nascent transcription and leads to markedly reduced expression of putative target genes. Epigenome silencing of these repeat sites does not affect gene expression in unrelated cells, can prevent the induction of gene expression by EWS-FLI1, and, in the case of a GGAA repeat that controls SOX2 expression from a distance of 470 kb, is sufficient to impair the growth of Ewing sarcoma xenografts. Using an experimental approach that is broadly applicable to testing different types of repetitive genomic elements, our study directly demonstrates that specific repeat microsatellites can have critical gene regulation functions in cancer and thus represent tumor-specific vulnerabilities that may be exploited to develop new therapies.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
4.5
作者：
de Koning AP;Gu W;Castoe TA;Batzer MA;Pollock DD
通讯作者：
Pollock DD
DOI：
10.1186/s13046-016-0321-3
发表时间：
2016-03-11
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Ren C;Ren T;Yang K;Wang S;Bao X;Zhang F;Guo W
通讯作者：
Guo W
致癌EWS-FLI1蛋白在体内GGAA微卫星序列结合了潜在的转录激活函数。
影响因子：
3.7
作者：
Guillon N;Tirode F;Boeva V;Zynovyev A;Barillot E;Delattre O
通讯作者：
Delattre O
影响因子：
50.3
作者：
Riggi N;Knoechel B;Gillespie SM;Rheinbay E;Boulay G;Suvà ML;Rossetti NE;Boonseng WE;Oksuz O;Cook EB;Formey A;Patel A;Gymrek M;Thapar V;Deshpande V;Ting DT;Hornicek FJ;Nielsen GP;Stamenkovic I;Aryee MJ;Bernstein BE;Rivera MN
通讯作者：
Rivera MN