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

被引:228
作者
McGarvey, KM
Fahrner, JA
Greene, E
Martens, J
Jenuwein, T
Baylin, SB
机构
[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA
[2] Johns Hopkins Univ, Sch Med, Grad Program Cellular & Mol Med, Baltimore, MD 21231 USA
[3] Res Inst Mol Pathol, Vienna Bioctr, A-1030 Vienna, Austria
关键词
D O I
10.1158/0008-5472.CAN-05-2481
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 at euchromatic state. When the aberrantly silenced gene is DNA demethylated and reexpressed following 5-aza-2'-deoxycytidine treatment, H3K9. 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.
引用
收藏
页码:3541 / 3549
页数:9
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