TY - JOUR
T1 - SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation
AU - Banine, Fatima
AU - Bartlett, Christopher
AU - Gunawardena, Ranjaka
AU - Muchardt, Christian
AU - Yaniv, Moshe
AU - Knudsen, Erik S.
AU - Weissman, Bernard E.
AU - Sherman, Larry S.
PY - 2005/5/1
Y1 - 2005/5/1
N2 - Brahma (Brm) and brahma-related gene-1 (Brg1) are mammalian homologues of SWI/SNF chromatin-remodeling factor subunits that can regulate both transcriptional activation and repression. Both Brg1 and Brm are mutated or deleted in numerous cancer cell lines, leading to the altered expression of genes that influence cell proliferation and metastasis. Here, we find that the promoters of two such genes, CD44 and E-cadherin, are hypermethylated in cells that have lost Brg1 or Brm. In two carcinoma cell lines that lack functional Brg1 and Brm, CD44 and E-cadherin expression are induced by the demethylating agent 5-aza-2′-deoxycytidine. Transfection with either Brg1 or Brm also induces CD44 and E-cadherin transcription and protein expression in these cells, as well as loss of methylation at sequences in the promoters of both genes. Chromatin immunoprecipitation assays show that Brg1 and Brm associate with these regions of the CD44 and E-cadherin promoters, suggesting that SWI/SNF protein complexes may directly influence the loss of DNA methylation. In vivo, Brm-deficient mice also show methylation and silencing of the CD44 promoter. Collectively, these data implicate loss of SWI/SNF-mediated transcriptional activation as a novel mechanism to increase DNA methylation in cancer cells and provide insight into the mechanisms underlying aberrant gene induction and repression during tumor progression.
AB - Brahma (Brm) and brahma-related gene-1 (Brg1) are mammalian homologues of SWI/SNF chromatin-remodeling factor subunits that can regulate both transcriptional activation and repression. Both Brg1 and Brm are mutated or deleted in numerous cancer cell lines, leading to the altered expression of genes that influence cell proliferation and metastasis. Here, we find that the promoters of two such genes, CD44 and E-cadherin, are hypermethylated in cells that have lost Brg1 or Brm. In two carcinoma cell lines that lack functional Brg1 and Brm, CD44 and E-cadherin expression are induced by the demethylating agent 5-aza-2′-deoxycytidine. Transfection with either Brg1 or Brm also induces CD44 and E-cadherin transcription and protein expression in these cells, as well as loss of methylation at sequences in the promoters of both genes. Chromatin immunoprecipitation assays show that Brg1 and Brm associate with these regions of the CD44 and E-cadherin promoters, suggesting that SWI/SNF protein complexes may directly influence the loss of DNA methylation. In vivo, Brm-deficient mice also show methylation and silencing of the CD44 promoter. Collectively, these data implicate loss of SWI/SNF-mediated transcriptional activation as a novel mechanism to increase DNA methylation in cancer cells and provide insight into the mechanisms underlying aberrant gene induction and repression during tumor progression.
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U2 - 10.1158/0008-5472.CAN-04-3554
DO - 10.1158/0008-5472.CAN-04-3554
M3 - Article
C2 - 15867346
AN - SCOPUS:18144362099
SN - 0008-5472
VL - 65
SP - 3542
EP - 3547
JO - Cancer research
JF - Cancer research
IS - 9
ER -