Cell
Volume 162, Issue 2, 16 July 2015, Pages 300-313
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Article
G1/S Inhibitors and the SWI/SNF Complex Control Cell-Cycle Exit during Muscle Differentiation

https://doi.org/10.1016/j.cell.2015.06.013Get rights and content
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Highlights

  • A combined conditional knockout and lineage-tracing system for C. elegans

  • Quantitative in vivo analysis of cell-cycle exit during development

  • SWI/SNF and G1/S inhibitors provide alternative mechanisms for cell-cycle arrest

  • The SWI/SNF complex prevents tumorous over-proliferation in C. elegans

Summary

The transition from proliferating precursor cells to post-mitotic differentiated cells is crucial for development, tissue homeostasis, and tumor suppression. To study cell-cycle exit during differentiation in vivo, we developed a conditional knockout and lineage-tracing system for Caenorhabditis elegans. Combined lineage-specific gene inactivation and genetic screening revealed extensive redundancies between previously identified cell-cycle inhibitors and the SWI/SNF chromatin-remodeling complex. Muscle precursor cells missing either SWI/SNF or G1/S inhibitor function could still arrest cell division, while simultaneous inactivation of these regulators caused continued proliferation and a C. elegans tumor phenotype. Further genetic analyses support that SWI/SNF acts in concert with hlh-1 MyoD, antagonizes Polycomb-mediated transcriptional repression, and suppresses cye-1 Cyclin E transcription to arrest cell division of muscle precursors. Thus, SWI/SNF and G1/S inhibitors provide alternative mechanisms to arrest cell-cycle progression during terminal differentiation, which offers insight into the frequent mutation of SWI/SNF genes in human cancers.

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