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法国PSL•巴黎文理研究大学Olivier Delattre和瑞士苏黎世大学Didier Surdez团队合作的最新研究发现在尤文氏肉瘤中，STAG2突变改变了CTCF锚定环挤出并减少顺式调节相互作用和EWSR1-FLI1活性。相关论文于2021年4月29日在线发表在《癌细胞》杂志上。

使用等基因尤文细胞，研究人员发现虽然STAG2功能丧失（LOF）突变显著该变了转录组，但它不会明显影响EWSR1-FLI1、CTCF /粘着蛋白或乙酰化H3K27 DNA的结合模式。相反，它严重改变了边界CTCF位点的锚定动态环挤出过程，并显著降低了启动子与增强子的相互作用，尤其是影响了EWSR1-FLI1调控基因在GGAA微卫星增强子上的表达。

在STAG2-LOF条件下观察到的顺式介导EWSR1-FLI1活性下调与以前在EWSR1-FLI1low细胞中观察到的尤文细胞迁移和侵袭特性增强相关。该研究阐明了一个过程，其中STAG2-LOF通过改变CTCF锚定环挤出和顺式介导的增强子机制来精密调控致癌转录因子的活性。

据介绍，粘附蛋白家族基因STAG2是癌症中最常发生突变的基因之一。STAG2功能丧失突变与尤文氏肉瘤的侵袭性有关，尤文氏肉瘤是由EWSR1-FLI1融合癌基因诱导异常转录产生的儿童期癌症。

附：英文原文

Title: STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma

Author: Didier Surdez, Sakina Zaidi, Sandrine Grossetête, Karine Laud-Duval, Anna Sole Ferre, Lieke Mous, Thomas Vourch, Franck Tirode, Gaelle Pierron, Virginie Raynal, Sylvain Baulande, Erika Brunet, Véronique Hill, Olivier Delattre

Issue&Volume: 2021-04-29

Abstract: STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, achildhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1,CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly altersthe anchored dynamic loop extrusion process at boundary CTCF sites and dramaticallydecreases promoter-enhancer interactions, particularly affecting the expression ofgenes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulationof cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewingcells previously observed in EWSR1-FLI1low cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through alteredCTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.

DOI: 10.1016/j.ccell.2021.04.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00208-7

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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