Regulation of the Wnt signaling pathway during myogenesis by the mammalian SWI/SNF ATPase BRG1.
Regulation of the Wnt signaling pathway during myogenesis by the mammalian SWI/SNF ATPase BRG1.
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DOI：
10.3389/fcell.2023.1160227
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发表时间：
2023
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
骨骼肌分化是一个受到严格调控的过程，哺乳动物SWI/SNF（mSWI/SNF）染色质重塑家族对骨骼肌发生相关基因调控的重要性已得到充分证实。我们之前的工作表明，mSWI/SNF ATP酶BRG 1和BRM的布罗莫结构域通过促进mSWI/SNF酶与生肌基因和其他靶基因的调节区域结合来促进肌生成。在这里，我们报告的差异表达基因的通路分析，该研究确定了一个额外的作用mSWI/SNF酶通过Wnt信号通路的调节。Wnt通路以前已被证明对骨骼肌发育很重要。为了研究mSWI/SNF酶对Wnt途径调节的重要性，对BRG 1和BRM进行单独和双重敲低，然后进行RNA测序。结果表明，BRG 1，而不是BRM，是Wnt途径组分和下游基因的调节剂。通过稳定β-连环蛋白重新激活Wnt途径可以挽救由于BRG 1敲低或使用特异性小分子抑制剂PFI-3抑制布罗莫结构域而导致的肌源性基因表达和分化的缺陷。这些结果表明BRG 1是β-连环蛋白功能上游所必需的。BRG 1、BRM和β-catenin在Wnt通路组分基因启动子处的染色质免疫沉淀显示BRG 1和β-catenin结合，这为这些基因的转录调控提供了进一步的机制见解。
Skeletal muscle differentiation is a tightly regulated process, and the importance of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling family for regulation of genes involved in skeletal myogenesis is well-established. Our prior work showed that bromodomains of mSWI/SNF ATPases BRG1 and BRM contribute to myogenesis by facilitating the binding of mSWI/SNF enzymes to regulatory regions of myogenic and other target genes. Here, we report that pathway analyses of differentially expressed genes from that study identified an additional role for mSWI/SNF enzymes via the regulation of the Wnt signaling pathway. The Wnt pathway has been previously shown to be important for skeletal muscle development. To investigate the importance of mSWI/SNF enzymes for the regulation of the Wnt pathway, individual and dual knockdowns were performed for BRG1 and BRM followed by RNA-sequencing. The results show that BRG1, but not BRM, is a regulator of Wnt pathway components and downstream genes. Reactivation of Wnt pathway by stabilization of β-catenin could rescue the defect in myogenic gene expression and differentiation due to BRG1 knockdown or bromodomain inhibition using a specific small molecule inhibitor, PFI-3. These results demonstrate that BRG1 is required upstream of β-catenin function. Chromatin immunoprecipitation of BRG1, BRM and β-catenin at promoters of Wnt pathway component genes showed binding of BRG1 and β-catenin, which provides further mechanistic insight to the transcriptional regulation of these genes.
影响因子：
8
作者：
Pansters, N. A. M.;van der Velden, J. L. J.;Kelders, M. C. J. M.;Laeremans, H.;Schols, A. M. W. J.;Langen, R. C. J.
通讯作者：
Langen, R. C. J.