The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells

Here, we expose the connection between rSWI/SNF and oncogenic processes using a well-characterized chemical degrader to deplete the SWI/SNF ATPase, BRG1. Using a combination of gene expression and chromatin accessibility assays we show that rSWI/SNF complexes facilitate MYC target gene expression. We also find that rSWI/SNF maintains open chromatin at sites associated with hallmark cancer genes linked to the AP-1 transcription factor, suggesting that AP-1 may drive oncogenesis in MRT. We used a well-characterized chemical degrader targeted against the SWI/SNF ATPase, BRG1 to deplete BRG1 in the G401 MRT cell line. For RNA-seq and ATAC-seq, G401 cells were treated for 24 hours with 250 nM ACBI1 or matched DMSO control.

本研究借助一款经过充分表征的化学降解剂降解SWI/SNF ATP酶 (SWI/SNF ATPase) BRG1，揭示了rSWI/SNF与肿瘤发生进程之间的关联。通过联合运用基因表达检测 (gene expression assays) 与染色质可及性检测 (chromatin accessibility assays)，本研究证实rSWI/SNF复合物可促进MYC靶基因的表达。此外，我们发现rSWI/SNF能够在与AP-1转录因子 (AP-1 transcription factor) 相关的标志性癌基因位点维持染色质开放状态，这提示AP-1可能在MRT中驱动肿瘤发生。本研究使用前述经过充分表征的、靶向SWI/SNF ATP酶BRG1的化学降解剂，在G401 MRT细胞系中实现了BRG1的降解。针对RNA测序 (RNA-seq) 与转座酶可及性染色质测序 (ATAC-seq) 实验，我们将G401细胞以250 nM的ACBI1或等体积二甲基亚砜 (DMSO) 对照处理24小时。