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Molecular and Cellular Biology, May 2008, p. 3457-3464, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02019-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

SWI/SNF Mediates Polycomb Eviction and Epigenetic Reprogramming of the INK4b-ARF-INK4a Locus{triangledown}

Sima Kheradmand Kia, Marcin M. Gorski, Stavros Giannakopoulos, and C. Peter Verrijzer*

Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

Received 9 November 2007/ Returned for modification 29 November 2007/ Accepted 14 February 2008

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 p16INK4a 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 p15INK4b and p16INK4a, but not of p14ARF. 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.

* Corresponding author. Mailing address: Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: (31) 10-408-7326. Fax: (31) 10-7044747. E-mail: c.verrijzer{at}erasmusmc.nl

{triangledown} Published ahead of print on 10 March 2008.

Molecular and Cellular Biology, May 2008, p. 3457-3464, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02019-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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