SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [primary tissue_ChIP-seq]. Homo sapiens

SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1. Overall design: ChIP-seq of three histone modifications: H3K27ac, H3K4m3, H3K4me1 in primary Rhabdoid tumor samples

SWI/SNF（BAF）染色质重塑复合物的核心亚基SMARCB1（SNF5/INI1/BAF47）在几乎所有儿童横纹肌样瘤中均发生失活。这类侵袭性癌症属于基因组最稳定的肿瘤类型之一，提示SMARCB1缺失可通过表观遗传机制驱动肿瘤转化。本研究发现，尽管人类横纹肌样瘤的突变谱无显著差异，但其展现出独特的增强子H3K27ac特征，该特征可反映分化程序的残留痕迹。我们证实，SMARCB1对SWI/SNF复合物的完整性至关重要；其缺失会改变增强子靶向模式，显著削弱SWI/SNF与典型增强子的结合——尤其是那些参与分化调控的典型增强子，同时却保留了SWI/SNF在超级增强子处的结合。我们进一步发现，这些保留的超级增强子对横纹肌样瘤的存活必不可少，其中既包括跨所有亚型共有的超级增强子（如SPRY1），也包括谱系特异性超级增强子（如脑源性横纹肌样瘤中的SOX2）。综上，本研究揭示了SMARCB1抑癌活性背后一种全新的染色质相关表观遗传机制。实验设计：对原发性横纹肌样瘤样本开展染色质免疫共沉淀测序（ChIP-seq），检测三种组蛋白修饰：H3K27ac、H3K4m3及H3K4me1。