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Regulation of the Wnt signaling pathway during myogenesis by the mammalian SWI/SNF ATPase BRG1

Sharma, Tapan
Olea-Flores, Monserrat
Imbalzano, Anthony N.
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Journal Article
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2023-07-07
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Abstract

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.

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Sharma T, Olea-Flores M, Imbalzano AN. Regulation of the Wnt signaling pathway during myogenesis by the mammalian SWI/SNF ATPase BRG1. Front Cell Dev Biol. 2023 Jul 7;11:1160227. doi: 10.3389/fcell.2023.1160227. PMID: 37484913; PMCID: PMC10360407.

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DOI
10.3389/fcell.2023.1160227
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37484913
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© 2023 Sharma, Olea-Flores and Imbalzano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Attribution 4.0 International