Scientific article

Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin

Published inNature Genetics, vol. 49, no. 2, p. 282-288
Publication date2017

Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs). This opposition underlies the tumor-suppressive role of BAF subunits and is expected to contribute to neurodevelopmental disorders. However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF-PRC opposition underlying development and disease.

  • Adenosine Triphosphatases/genetics
  • Adenosine Triphosphate/genetics
  • Animals
  • Cell Cycle Proteins/genetics
  • Chromatin/genetics
  • Chromatin Assembly and Disassembly/genetics
  • DNA Helicases/genetics
  • DNA-Binding Proteins/genetics
  • Mice
  • Neurodevelopmental Disorders/genetics
  • Nuclear Proteins/genetics
  • Point Mutation/genetics
  • Polycomb-Group Proteins/genetics
  • Transcription Factors/genetics
Affiliation Not a UNIGE publication
Citation (ISO format)
STANTON, Benjamin Z et al. Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. In: Nature Genetics, 2017, vol. 49, n° 2, p. 282–288. doi: 10.1038/ng.3735
Main files (1)
Article (Published version)
ISSN of the journal1061-4036

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