Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunitSMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1—which becomes essential in the absence ofSMARCB1—but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression inSMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs.
SWI/SNF染色质重塑复合体突变发生于约20%的癌症中。在以SWI/SNF亚基SMARCB1缺失为特征的非典型畸胎样/横纹肌样瘤中，增强子介导的基因表达失调是驱动肿瘤发生的关键因素。在此背景下，增强子失调与SWI/SNF ATP酶BRG1的保留密切相关——该酶在SMARCB1缺失条件下变得不可或缺——但BRG1如何具体参与这一过程尚不明确。为阐明BRG1在SMARCB1缺陷细胞中如何参与染色质重塑与基因表达调控，我们对多种横纹肌样瘤细胞系进行了BRG1缺失影响的基因组水平表征分析。研究发现，虽然BRG1调控的开放染色质位点在基因座层面具有特异性，但这些位点的生物学特征高度相似，均汇聚于一组主题相关的基因群，并指向AP-1转录因子的参与。BRG1调控的开放染色质位点与组蛋白标记的增强子共定位，且显著涵盖了几乎所有超级增强子，揭示BRG1在该背景下对维持超级增强子功能具有关键作用。这些研究能够解释BRG1对横纹肌样瘤细胞特性与存活的核心必要性，并提示AP-1作为横纹肌样瘤细胞转录程序关键下游效应因子的参与机制。
Super-Enhancer Dysregulation in Rhabdoid Tumor Cells Is Regulated by the SWI/SNF ATPase BRG1
肿瘤(癌症)患者之家