title: SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus.
abstract: Stable silencing of the INK4b-ARF-INK4a tumor suppressor locus occurs in a variety of human cancers, including malignant rhabdoid tumors (MRTs). MRTs are extremely aggressive cancers caused by the loss of the hSNF5 subunit of the SWI/SNF chromatin-remodeling complex. We found previously that, in MRT cells, hSNF5 is required for p16(INK4a) induction, mitotic checkpoint activation, and cellular senescence. Here, we investigated how the balance between Polycomb group (PcG) silencing and SWI/SNF activation affects epigenetic control of the INK4b-ARF-INK4a locus in MRT cells. hSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15(INK4b) and p16(INK4a), but not of p14(ARF). Gene activation by hSNF5 is strictly dependent on the SWI/SNF motor subunit BRG1. SWI/SNF mediates eviction of the PRC1 and PRC2 PcG silencers and extensive chromatin reprogramming. Concomitant with PcG complex removal, the mixed lineage leukemia 1 (MLL1) protein is recruited and active histone marks supplant repressive ones. Strikingly, loss of PcG complexes is accompanied by DNA methyltransferase DNMT3B dissociation and reduced DNA methylation. Thus, various chromatin states can be modulated by SWI/SNF action. Collectively, these findings emphasize the close interconnectivity and dynamics of diverse chromatin modifications in cancer and gene control.
authors.affiliation: Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Sima Kheradmand
authors.initials: SK
authors.lastname: Kia
authors.forename: Marcin M
authors.initials: MM
authors.lastname: Gorski
authors.forename: Stavros
authors.initials: S
authors.lastname: Giannakopoulos
authors.forename: C Peter
authors.initials: CP
authors.lastname: Verrijzer
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018335:Rhabdoid Tumor / Q000235:genetics / Q000378:metabolism; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C493966:CDKN2B protein, human; D002868:Chromosomal Proteins, Non-Histone; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases