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Papers In Press, published online ahead of print December 3, 2001
J. Biol. Chem, 10.1074/jbc.M109809200
Submitted on October 10, 2001
Revised on November 28, 2001
Accepted on December 3, 2001

Methylation-mediated silencing of TMS1/ASC is accompanied by histone hypoacetylation and CpG island-localized changes in chromatin architecture

Krista M. Stimson and Paula M. Vertino

Winship Cancer Institute, Emory University, Atlanta, GA 30322

Corresponding Author: pvertin{at}emory.edu

Aberrant methylation of CpG dense islands in the promoter regions of genes is an acquired epigenetic alteration associated with the silencing of tumor suppressor genes in human cancers. In a screen for endogenous targets of methylation-mediated gene silencing, we identified a novel CpG island-associated gene, TMS1, that is aberrantly methylated and silenced in response to the ectopic expression of DNA methyltransferase-1. In this study, we characterized the methylation pattern and chromatin architecture of the TMS1 locus in normal fibroblasts and determined the changes associated with its progressive methylation. In normal fibroblasts expressing TMS1, the CpG island is defined by an unmethylated domain that is separated from densely methylated flanking DNA by distinct 5' and 3' boundaries. Analysis of the nucleoprotein architecture of the locus in intact nuclei revealed three DNAse I hypersensitive sites that map to within the CpG island. Strikingly, two of these sites coincided with the 5' and 3' methylation boundaries. Methylation of the TMS1 CpG island was accompanied by loss of hypersensitive site formation, hypoacetylation of histones H3 and H4, and gene silencing. This altered chromatin structure was confined to the CpG island, and occurred without significant changes in methylation, histone acetylation or hypersensitive site formation at a fourth DNAse I hypersensitive site 2 kb downstream of the TMS1 CpG island. The data indicate that there are sites of protein binding and/or structural transitions that define the boundaries of the unmethylated CpG island in normal cells, and that aberrant methylation overcomes these boundaries to direct a local change in chromatin structure, resulting in gene silencing.


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