SWI/SNF Chromatin-Remodeling Factors Induce Changes in DNA Methylation to Promote Transcriptional Activation

Abstract

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 Ecadherin, 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-2V -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 Ecadherin 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. (Cancer Res 2005; 65(9): 3542-7)

Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP

“…cAMP could lead, through the phosphoacetylation of histone H3, to a broad expression of trans-acting factors, 43,44 enabling their recruitment at specific sites on the CD44 promoter. 45,46 In particular, our findings are reminiscent of the study by Hyman et al 45 showing that the transcription factor c-Jun was involved in transcriptional reactivation of the silenced CD44 gene, whereas its promoter is still fully methylated. We further checked whether c-Jun expression is modulated by cAMP in NB4-LR1 cells, and analysed the ability of this transcription factor to bind CD44 promoter.…”

“…It has been recently described to contribute to the crosstalk between transcription and RNA Pol II processing and to be directly involved in the re-activation of CD44 in a carcinoma cell line where CD44 transcription was silenced by hypermethylation of CpG island within its promoter. 46,47 In NB4-LR1 cells, Brm is expressed at transcriptional and protein levels (Figures 6a and b), without modulation of its expression by cAMP. ChIP assays reveal that, in 48 h-cAMPtreated cells, Brm protein interacts with CD44 promoter, whereas no interaction is detectable in untreated cells (Figure 6c).…”

ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1

“…SWI/SNF complexes have been associated with demethylation of E-cadherin and CD44 genes (Banine et al, 2005) although interactions of SWI/SNF with At 48 h, cell lysates were loaded into polyacrylamide gels and protein levels were assessed by WB with the corresponding Abs as described in Supplementary Information. (b) BRG1 is required for efficient repression of endogenous E-cadherin and induction of EMT by ZEB1.…”

The SWI/SNF complex and cancer

“…The exact genes underlying these phenomena are not completely known. However, the cell-adhesion proteins CD44 and E-cadherin are regulated by SWI/SNF (Banine et al, 2005). CD44 transcription appears to require SWI/SNF activity, but the regulation of E-cadherin expression appears to be more complex and may involve splicing (Batsche et al, 2006).…”