title: Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin.
abstract: 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.
authors.affiliation: Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.|Systems Biology Center, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Benjamin Z
authors.initials: BZ
authors.lastname: Stanton
authors.affiliation: Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Courtney
authors.identifier: http://orcid.org/0000-0003-4441-497X
authors.initials: C
authors.lastname: Hodges
authors.affiliation: Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Calarco
authors.affiliation: Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Simon M G
authors.initials: SM
authors.lastname: Braun
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wai Lim
authors.initials: WL
authors.lastname: Ku
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Cigall
authors.identifier: http://orcid.org/0000-0002-4058-5985
authors.initials: C
authors.lastname: Kadoch
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Crabtree
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D051379:Mice; D065886:Neurodevelopmental Disorders / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D063146:Polycomb-Group Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C513194:Smarca4 protein, mouse; D004265:DNA Helicases