SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation.
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.
Banine
Fatima
F
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA.
Bartlett
Christopher
C
Gunawardena
Ranjaka
R
Muchardt
Christian
C
Yaniv
Moshe
M
Knudsen
Erik S
ES
Weissman
Bernard E
BE
Sherman
Larry S
LS
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004265:DNA Helicases; D019175:DNA Methylation; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection
D002868:Chromosomal Proteins, Non-Histone; D018960:Hyaluronan Receptors; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases