STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.
STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.
复制标题
DOI：
10.1016/j.ccell.2021.05.007
复制
发表时间：
2021-06-14
期刊：
影响因子：
50.3
通讯作者：
Stegmaier K
中科院分区：
文献类型：
--
作者：
Adane B;Alexe G;Seong BKA;Lu D;Hwang EE;Hnisz D;Lareau CA;Ross L;Lin S;Dela Cruz FS;Richardson M;Weintraub AS;Wang S;Iniguez AB;Dharia NV;Conway AS;Robichaud AL;Tanenbaum B;Krill-Burger JM;Vazquez F;Schenone M;Berman JN;Kung AL;Carr SA;Aryee MJ;Young RA;Crompton BD;Stegmaier K
核心粘连蛋白亚基STAG 2在尤文肉瘤中反复突变，但其生物学作用尚不清楚。在此，我们证明了含有STAG 2的粘附素复合物占据增强子和多梳抑制复合物（PRC 2）标记的调控区域。STAG 2的遗传抑制导致粘着蛋白-STAG 1复合物的补偿性增加，但不是在增强子丰富的区域，并导致顺式染色质相互作用的重编程。引人注目的是，在STAG 2敲除细胞中，由融合转录因子EWS/FLI 1驱动的致癌遗传程序受到高度干扰，部分原因是增强子-启动子接触改变。此外，STAG 2的缺失也破坏了PRC 2介导的基因表达调控。结合起来，这些转录变化集中在调节EWS/FLI 1，迁移和神经发育程序。最后，与临床观察一致，功能研究表明STAG 2的缺失增强了尤文肉瘤异种移植物的转移潜力。我们的研究结果表明，STAG 2突变可以改变染色质结构和转录程序，以促进侵袭性癌症表型。Adane等人证明，STAG 2的缺失改变了尤文肉瘤中粘附素复合物的分布，并导致顺式染色质相互作用的重编程。STAG 2缺失减弱了EWS/FLI 1驱动的致癌程序，并破坏了PRC 2调节的发育过程，以增强尤文肉瘤细胞的转移潜力。
The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Herein, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2) marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells, the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype. Adane et al. demonstrate that deletion of STAG2 changes the distribution of cohesin complexes and leads to reprograming of cis-chromatin interactions in Ewing sarcoma. STAG2 loss attenuated EWS/FLI1 driven oncogenic programs and disrupted PRC2 regulated developmental processes to enhance the metastatic potential of Ewing sarcoma cells.
登录
查看更多内容
影响因子：
--
作者：
Benedetti L;Cereda M;Monteverde L;Desai N;Ciccarelli FD
通讯作者：
Ciccarelli FD
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
64.5
作者：
Dowen JM;Fan ZP;Hnisz D;Ren G;Abraham BJ;Zhang LN;Weintraub AS;Schujiers J;Lee TI;Zhao K;Young RA
通讯作者：
Young RA
影响因子：
9.8
作者：
Haldi, Maryann;Ton, Christopher;McGrath, Patricia
通讯作者：
McGrath, Patricia
影响因子：
8
作者：
Franzetti GA;Laud-Duval K;van der Ent W;Brisac A;Irondelle M;Aubert S;Dirksen U;Bouvier C;de Pinieux G;Snaar-Jagalska E;Chavrier P;Delattre O
通讯作者：
Delattre O