title: SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation.
abstract: SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting-markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Burak H
authors.initials: BH
authors.lastname: Alver
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Haswell
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Jakub
authors.initials: J
authors.lastname: Mieczkowski
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Yotam
authors.identifier: http://orcid.org/0000-0003-1725-2995
authors.initials: Y
authors.lastname: Drier
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
authors.affiliation: Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tenley C
authors.initials: TC
authors.lastname: Archer
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Wu
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Evgeni P
authors.initials: EP
authors.lastname: Tzvetkov
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Troisi
authors.affiliation: Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine at the University of Southern California, Los Angeles, California, USA.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Biegel
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tolstorukov
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Peter J
authors.identifier: http://orcid.org/0000-0001-9378-960X
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D018335:Rhabdoid Tumor / Q000235:genetics; D000071796:SMARCB1 Protein / Q000235:genetics*
chemical_list: C501959:BANF1 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human