SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus.

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  • Author(s): Kia SK;Kia SK; Gorski MM; Giannakopoulos S; Verrijzer CP
  • Source:
    Molecular and cellular biology [Mol Cell Biol] 2008 May; Vol. 28 (10), pp. 3457-64. Date of Electronic Publication: 2008 Mar 10.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: United States NLM ID: 8109087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5549 (Electronic) Linking ISSN: 02707306 NLM ISO Abbreviation: Mol Cell Biol Subsets: MEDLINE
    • Publication Information:
      Publication: 2023- : [Philadelphia] : Taylor & Francis
      Original Publication: [Washington, D.C.] : American Society for Microbiology, [c1981-
    • Subject Terms:
      Epigenesis, Genetic*; Cyclin-Dependent Kinase Inhibitor p15/*metabolism ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Repressor Proteins/*metabolism ; Transcription Factors/*metabolism; Base Sequence ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Cyclin-Dependent Kinase Inhibitor p15/genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; DNA Helicases/genetics ; DNA Helicases/metabolism ; DNA Methylation ; DNA Primers/genetics ; DNA, Neoplasm/chemistry ; DNA, Neoplasm/genetics ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Silencing ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Polycomb-Group Proteins ; Promoter Regions, Genetic ; Repressor Proteins/genetics ; Rhabdoid Tumor/genetics ; Rhabdoid Tumor/metabolism ; SMARCB1 Protein ; Transcription Factors/genetics
    • 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.
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    • Accession Number:
      0 (CDKN2B protein, human)
      0 (Chromosomal Proteins, Non-Histone)
      0 (Cyclin-Dependent Kinase Inhibitor p15)
      0 (Cyclin-Dependent Kinase Inhibitor p16)
      0 (DNA Primers)
      0 (DNA, Neoplasm)
      0 (DNA-Binding Proteins)
      0 (Nuclear Proteins)
      0 (Polycomb-Group Proteins)
      0 (Repressor Proteins)
      0 (SMARCB1 Protein)
      0 (SMARCB1 protein, human)
      0 (Transcription Factors)
      EC 3.6.1.- (SMARCA4 protein, human)
      EC 3.6.4.- (DNA Helicases)
    • Publication Date:
      Date Created: 20080312 Date Completed: 20080514 Latest Revision: 20211020
    • Publication Date:
      20240829
    • Accession Number:
      PMC2423153
    • Accession Number:
      10.1128/MCB.02019-07
    • Accession Number:
      18332116