Fukushige Shinichi, Kondo Emiko, Horii Akira
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Biochem Biophys Res Commun. 2008 Dec 12;377(2):600-605. doi: 10.1016/j.bbrc.2008.10.016. Epub 2008 Oct 16.
DNA methylation and histone modifications are both major features of the epigenetic silencing seen at tumor suppressor genes (TSGs) in cancer. DNA methylation inhibitors, but not, in general, histone deacetylase, can reactivate TSGs. However, DNA methylation inhibitors frequently upregulate genes whose promoters remain unmethylated. Herein we demonstrated that the methyl-CpG targeted transcriptional activation (MeTA), which allows re-expression of TSGs without DNA demethylation, is widely seen in human cancer. We further analyzed MeTA and found that transcriptional coactivators are recruited at hypermethylated promoter regions of TSGs using the methyl-CpG binding domain (MBD). Reactivation of MLH1 by MeTA accompanied acetylation of histone H3 lysine 9/14 at the promoter region. Furthermore, all ten genes analyzed in three cell lines were reactivated by the effect of MeTA. Our present results lead to an efficient way to search for transcriptionally silenced genes with highly methylated CpG islands, particularly TSGs in cancer and developmentally important genes in embryonic stem cells.
DNA甲基化和组蛋白修饰都是癌症中肿瘤抑制基因（TSGs）表观遗传沉默的主要特征。DNA甲基化抑制剂通常能重新激活TSGs，但组蛋白去乙酰化酶一般不能。然而，DNA甲基化抑制剂经常会上调其启动子未甲基化的基因。在此我们证明，甲基化CpG靶向转录激活（MeTA），即无需DNA去甲基化就能重新表达TSGs，在人类癌症中广泛存在。我们进一步分析了MeTA，发现转录共激活因子通过甲基化CpG结合域（MBD）被招募到TSGs的高甲基化启动子区域。MeTA对MLH1的重新激活伴随着启动子区域组蛋白H3赖氨酸9/14的乙酰化。此外，在三个细胞系中分析的所有十个基因都因MeTA的作用而被重新激活。我们目前的结果为寻找具有高度甲基化CpG岛的转录沉默基因提供了一种有效的方法，特别是癌症中的TSGs和胚胎干细胞中对发育重要的基因。
