Although ARID1A mutations are a hallmark feature, mutations in other SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling subunits are also observed in endometrial neoplasms. Here, we interrogated the roles of Brahma/SWI2-related gene 1 (BRG1, SMARCA4), the SWI/SNF catalytic subunit, in the endometrial epithelium. BRG1 loss affects more than one-third of all active genes and highly overlaps with the ARID1A gene regulatory network. Chromatin immunoprecipitation studies revealed widespread subunit-specific differences in transcriptional regulation, as BRG1 promoter interactions are associated with gene activation, while ARID1A binding is associated with gene repression. However, we identified a physiologically relevant subset of BRG1 and ARID1A co-regulated epithelial identity genes. Mice were genetically engineered to inactivate BRG1 specifically in the endometrial epithelium. Endometrial glands were observed embedded in uterine myometrium, indicating adenomyosis-like phenotypes. Molecular similarities were observed between BRG1 and ARID1A mutant endometrial cells in vivo, including loss of epithelial cell adhesion and junction genes. Collectively, these studies illustrate overlapping contributions of multiple SWI/SNF subunit mutations in the translocation of endometrium to distal sites, with loss of cell integrity being a common feature in SWI/SNF mutant endometrial epithelia.

中文翻译：

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子宫内膜上皮中的 SWI/SNF 失活导致上皮完整性丧失

虽然ARID1A突变是一个标志性特征，在子宫内膜肿瘤中也观察到其他 SWI/SNF（SWItch/Sucrose Non-Fermentable）染色质重塑亚基的突变。在这里，我们询问了 Brahma/SWI2 相关基因 1（BRG1、SMARCA4）、SWI/SNF 催化亚基在子宫内膜上皮细胞中的作用。BRG1 损失影响超过三分之一的所有活性基因，并与 ARID1A 基因调控网络高度重叠。染色质免疫沉淀研究揭示了转录调控中广泛的亚基特异性差异，因为 BRG1 启动子相互作用与基因激活相关，而 ARID1A 结合与基因抑制相关。然而，我们确定了 BRG1 和 ARID1A 共同调节的上皮身份基因的生理相关子集。小鼠经过基因工程改造，可以使子宫内膜上皮细胞中的 BRG1 失活。观察到子宫内膜腺体嵌入子宫肌层，表明子宫腺肌病样表型。在 BRG1 和 ARID1A 突变子宫内膜细胞之间观察到分子相似性体内，包括上皮细胞粘附和连接基因的丧失。总的来说，这些研究说明了多个 SWI/SNF 亚基突变在子宫内膜向远端部位的易位中的重叠贡献，细胞完整性的丧失是 SWI/SNF 突变子宫内膜上皮细胞的一个共同特征。