Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo

Abstract

SWI/SNF (switch/sucrose nonfermenting) complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb group (PcG) proteins. Genes encoding SWI/SNF components are critical for normal development and frequently mutated in human cancer. We characterized the in vivo contributions of SWI/SNF and PcG complexes to proliferation-differentiation decisions, making use of the reproducible development of the nematode Caenorhabditis elegans. RNA interference, lineage-specific gene knockout, and targeted degradation of SWI/SNF BAF components induced either overproliferation or acute proliferation arrest of precursor cells, depending on residual protein levels. Our data show that a high SWI/SNF BAF dosage is needed to arrest cell division during differentiation and to oppose PcG-mediated repression. In contrast, a low SWI/SNF protein level is necessary to sustain cell proliferation and hyperplasia, even when PcG repression is blocked. These observations show that incomplete inactivation of SWI/SNF components can eliminate a tumor-suppressor activity while maintaining an essential transcription regulatory function.

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasionin vivo

“…the time of invasion. In addition to reflecting the dose-dependent nature of the SWI/SNF ATPase in cancer, our data in the AC is consistent with work done in C. elegans early mesoblast development where complete loss of the swsn-4 ATPase using a catalytically dead mutant and lineage-specific knockout strategy results in loss of cell cycle arrest (34). A limitation to our experimental strategy is that we cannot be sure that combining swsn-4 RNAi with an anti-GFP-targeting nanobody to deplete the SWI/SNF ATPase represents a null phenotype, as we limited our analysis to quantitative fluorescence measurements.…”

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made (31,(45)(46)(47), and cell cycle control (34,(48)(49)(50)(51), we chose to focus our efforts on characterizing the role of the SWI/SNF complex in promoting AC invasion.…”

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made (34,48,(54)(55)(56)(57)(58)(59).…”

“…The degree to which the SWI/SNF complex contributes to tumorigenesis in clinical settings has been linked to the dose of functional SWI/SNF ATPase in precancerous and transformed cells (31,33,62). Previous work in C. elegans has demonstrated a similar dose-dependent relationship between SWI/SNF and cell cycle control (34). We modulated expression of SWSN-4::GFP using a combination of RNAimediated knockdown and AC specific GFP-targeting nanobody technology to determine whether the phenotypic dosage-sensitivity seen in cancer and C. elegans mesodermal .…”

“…In yeast, Remodeling the Structure of Chromatin (RSC), the homologous complex to PBAF, is required for progression through mitosis (68,69). In Drosophila, the homologous complex PBAP is not required and cell cycle progression and G 2 /M transition is solely regulated by the BAF/BAP assembly (51) the C. elegans M lineage, RNAi-mediated loss of BAF results in hyperproliferation of the developing tissue, whereas knockdown of PBAF-specific subunits has little effect on cell cycle control (34). Similarly, in this study, RNAi-mediated loss of PBAF subunits pbrm-1, swsn-7, and swsn-9 only resulted in single non-invasive cells expressing the AC reporter.…”