| Autor: |
Smith, Jayson J., Xiao, Yutong, Parsan, Nithin, Medwig-Kinney, Taylor N., Martinez, Michael A. Q., Moore, Frances E. Q., Palmisano, Nicholas J., Kohrman, Abraham Q., Chandhok Delos Reyes, Mana, Adikes, Rebecca C., Liu, Simeiyun, Bracht, Sydney A., Zhang, Wan, Wen, Kailong, Kratsios, Paschalis, Matus, David Q. |
| Předmět: |
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| Zdroj: |
PLoS Genetics; 1/4/2022, Vol. 18 Issue 1, p1-35, 35p |
| Abstrakt: |
Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis. Author summary: Cellular invasion is required for animal development and homeostasis. Inappropriate activation of invasion however can result in cancer metastasis. Invasion programs are orchestrated by complex gene regulatory networks (GRN) that function in a coordinated fashion to turn on and off pro-invasive genes. While the core of GRNs are DNA binding transcription factors, they require aid from chromatin remodelers to access the genome. To identify the suite of pro-invasive chromatin remodelers, we paired high resolution imaging with RNA interference to individually knockdown 269 chromatin factors, identifying the evolutionarily conserved SWItching defective/Sucrose Non-Fermenting (SWI/SNF) ATP-dependent chromatin remodeling complex as a new regulator of Caenorhabditis elegans anchor cell (AC) invasion. Using a combination of CRISPR/Cas9 genome engineering and targeted protein degradation we demonstrate that the core SWI/SNF complex functions in a dose-dependent manner to control invasion. Further, we determine that the accessory SWI/SNF complexes, BAF and PBAF, contribute to invasion via distinctive mechanisms: BAF is required to prevent inappropriate proliferation while PBAF promotes AC attachment and remodeling of the basement membrane. Together, our data provide insights into how the SWI/SNF complex, which is mutated in many human cancers, can function in a dose-dependent fashion to regulate switching from invasive to proliferative fates. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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