G1/S Inhibitors and the SWI/SNF Complex Control Cell-Cycle Exit During Muscle Differentiation

Cell. 2015 Jul 16;162(2):300-313. doi: 10.1016/j.cell.2015.06.013. Epub 2015 Jul 2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / cytology*
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Cycle
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Chromosomal Proteins, Non-Histone / metabolism
  • Muscle Proteins
  • Muscles / cytology*
  • Muscles / metabolism
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Myogenic Regulatory Factors / metabolism
  • Nuclear Proteins
  • Polycomb-Group Proteins / metabolism
  • Transcription Factors / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Chromosomal Proteins, Non-Histone
  • Muscle Proteins
  • Myogenic Regulatory Factors
  • Nuclear Proteins
  • Polycomb-Group Proteins
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • HLH-1 protein, C elegans