Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo.
Aniek van der VaartMolly GodfreyVincent PortegijsSander van den HeuvelPublished in: Science advances (2020)
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.
Keyphrases
- cell proliferation
- cell cycle
- transcription factor
- signaling pathway
- genome wide
- single cell
- endothelial cells
- magnetic resonance
- dna methylation
- dna damage
- induced apoptosis
- gene expression
- machine learning
- cell cycle arrest
- binding protein
- big data
- electronic health record
- drug induced
- liver failure
- copy number
- genome wide identification
- protein protein
- bone marrow
- extracorporeal membrane oxygenation
- pluripotent stem cells
- endoplasmic reticulum stress