The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells.
The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells.
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SWI/SNF ATPase BRG1 促进 SMARCB1 缺陷癌细胞中的多种促肿瘤基因表达程序。
DOI：
10.1038/s41389-022-00406-6
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发表时间：
2022-06-01
期刊：
影响因子：
6.2
通讯作者：
Weissmiller, April M.
中科院分区：
文献类型：
--
作者：
Moe, Kylie C.;Maxwell, Jack N.;Wang, Jing;Jones, Cheyenne A.;Csaki, Grace T.;Florian, Andrea C.;Romer, Alexander S.;Bryant, Daniel L.;Farone, Anthony L.;Liu, Qi;Tansey, William P.;Weissmiller, April M.
恶性横纹肌样瘤（MRT）是由SWI/SNF染色质重塑复合物的SNF 5亚基的丢失驱动的，然后被认为是由残留的SWI/SNF（rSWI/SNF）复合物维持的，这些复合物在SNF 5不存在的情况下仍然存在。rSWI/SNF亚基与转录因子MYC广泛共定位在染色质上，MYC是一种被鉴定为MRT的新驱动因子的癌基因。目前，rSWI/SNF在调节MYC活性中的作用既没有被描述，也没有发现rSWI/SNF与其他癌基因之间的直接联系。在这里，我们暴露rSWI/SNF和致癌过程之间的联系，使用一种充分表征的化学降解剂耗尽SWI/SNF ATP酶，BRG 1。使用基因表达和染色质可及性分析的组合，我们表明，rSWI/SNF复合物促进MYC靶基因的表达。我们还发现，rSWI/SNF在与AP-1转录因子相关的标志性癌基因相关的位点保持开放的染色质，这表明AP-1可能驱动MRT中的肿瘤发生。有趣的是，MYC靶基因表达的变化与rSWI/SNF的染色质重塑功能没有明显联系，揭示了rSWI/SNF控制转录的多种机制。这项工作提供了一个了解如何残留SWI/SNF复合物可能会收敛于多个致癌过程时，正常SWI/SNF功能受损。
Malignant rhabdoid tumor (MRT) is driven by the loss of the SNF5 subunit of the SWI/SNF chromatin remodeling complex and then thought to be maintained by residual SWI/SNF (rSWI/SNF) complexes that remain present in the absence of SNF5. rSWI/SNF subunits colocalize extensively on chromatin with the transcription factor MYC, an oncogene identified as a novel driver of MRT. Currently, the role of rSWI/SNF in modulating MYC activity has neither been delineated nor has a direct link between rSWI/SNF and other oncogenes been uncovered. 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. Interestingly, changes in MYC target gene expression are not overtly connected to the chromatin remodeling function of rSWI/SNF, revealing multiple mechanisms used by rSWI/SNF to control transcription. This work provides an understanding of how residual SWI/SNF complexes may converge on multiple oncogenic processes when normal SWI/SNF function is impaired.
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影响因子：
21.3
作者：
Michel BC;D'Avino AR;Cassel SH;Mashtalir N;McKenzie ZM;McBride MJ;Valencia AM;Zhou Q;Bocker M;Soares LMM;Pan J;Remillard DI;Lareau CA;Zullow HJ;Fortoul N;Gray NS;Bradner JE;Chan HM;Kadoch C
通讯作者：
Kadoch C
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
15.9
作者：
Lee, Ryan S.;Stewart, Chip;Roberts, Charles W. M.
通讯作者：
Roberts, Charles W. M.
影响因子：
14.8
作者：
Nabet B;Roberts JM;Buckley DL;Paulk J;Dastjerdi S;Yang A;Leggett AL;Erb MA;Lawlor MA;Souza A;Scott TG;Vittori S;Perry JA;Qi J;Winter GE;Wong KK;Gray NS;Bradner JE
通讯作者：
Bradner JE
影响因子：
7.7
作者：
Kelso TWR;Porter DK;Amaral ML;Shokhirev MN;Benner C;Hargreaves DC
通讯作者：
Hargreaves DC