1. Academic Validation
  2. 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

  • Oncogenesis. 2022 Jun 1;11(1):30. doi: 10.1038/s41389-022-00406-6.
Kylie C Moe 1 Jack N Maxwell 1 Jing Wang 2 3 Cheyenne A Jones 1 Grace T Csaki 1 Andrea C Florian 4 Alexander S Romer 1 Daniel L Bryant 1 Anthony L Farone 1 Qi Liu 2 3 William P Tansey 4 5 April M Weissmiller 6
Affiliations

Affiliations

  • 1 Department of Biology, Middle Tennessee State University, Murfreesboro, TN, 32132, USA.
  • 2 Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37240, USA.
  • 3 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37240, USA.
  • 4 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, 37240, USA.
  • 5 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, 37240, USA.
  • 6 Department of Biology, Middle Tennessee State University, Murfreesboro, TN, 32132, USA. april.weissmiller@mtsu.edu.
Abstract

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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