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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state.

Authors: McGarvey, Kelly M; Fahrner, Jill A; Greene, Eriko; Martens, Joost; Jenuwein, Thomas; Baylin, Stephen B

Published In Cancer Res, (2006 Apr 1)

Abstract: Histone H3 lysine 9 (H3K9) and lysine 27 (H3K27) trimethylation are properties of stably silenced heterochromatin whereas H3K9 dimethylation (H3K9me2) is important for euchromatic gene repression. In colorectal cancer cells, all of these marks, as well as the key enzymes which establish them, surround the hMLH1 promoter when it is DNA hypermethylated and aberrantly silenced, but are absent when the gene is unmethylated and fully expressed in a euchromatic state. When the aberrantly silenced gene is DNA demethylated and reexpressed following 5-aza-2'-deoxycytidine treatment, H3K9me1 and H3K9me2 are the only silencing marks that are lost. A series of other silenced and DNA hypermethylated gene promoters behave identically even when the genes are chronically DNA demethylated and reexpressed after genetic knockout of DNA methyltransferases. Our data indicate that when transcription of DNA hypermethylated genes is activated in cancer cells, their promoters remain in an environment with certain heterochromatic characteristics. This finding has important implications for the translational goal of reactivating aberrantly silenced cancer genes as a therapeutic maneuver.

PubMed ID: 16585178 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing; Azacitidine/analogs & derivatives; Azacitidine/pharmacology; Carrier Proteins/genetics; Cell Line, Tumor; Chromatin/genetics*; Chromatin/metabolism; Colorectal Neoplasms/genetics*; Colorectal Neoplasms/metabolism; DNA Methylation*; Gene Silencing*; Genes, Tumor Suppressor*; HCT116 Cells; Histones/genetics; Histones/metabolism; Humans; Intercellular Signaling Peptides and Proteins/genetics; Membrane Proteins/genetics; Nuclear Proteins/genetics; Promoter Regions, Genetic

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