The thymine DNA glycosylase MBD4 represses transcription and is associated with methylated p16INK4a and hMLH1 genes
The thymine DNA glycosylase MBD4 represses transcription and is associated with methylated p16INK4a and hMLH1 genes
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DOI：
10.1128/mcb.25.11.4388-4396.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Fukushige, S
中科院分区：
文献类型：
--
作者：
Kondo, E;Gu, ZD;Fukushige, S
通过甲基 CpG (mCpG) 进行的表观遗传沉默与许多生物模式有关，例如基因组印记、X 染色体失活和癌症发展。在此过程中，mCpG 结合域 (MBD) 蛋白在将表观遗传信息传递给下游调节蛋白方面发挥着重要作用。迄今为止已发现的五种 MBD 蛋白中，MBD4 是唯一的例外。长期以来，它一直被认为是一种DNA修复蛋白。在此，我们证明 MBD4 具有通过 mCpG 抑制转录的能力。 MBD4 的转录抑制是组蛋白脱乙酰酶 (HDAC) 依赖性的，MBD4 在与转录抑制域重叠的三个中心区域直接与 Sin3A 和 HDAC1 结合。此外，染色质免疫沉淀分析清楚地表明 MBD4 与 p16(INK4a) 和 hMLH1 基因的高甲基化启动子结合。这些结果表明MBD4是参与癌症表观遗传沉默的重要成分之一，其修复活性对于维持高甲基化启动子是必需的。
Epigenetic silencing through methyl-CpG (mCpG) is implicated in many biological patterns such as genome imprinting, X chromosome inactivation, and cancer development. In this process, the mCpG binding domain (MBD) proteins play an essential role in transmitting epigenetic information to downstream regulatory proteins. Among the five MBD proteins identified so far, MBD4 has been the only exception; it has long been thought to be a DNA repair protein. Herein we demonstrate that MBD4 has the ability to repress transcription through mCpG. Transcriptional repression by the MBD4 is histone deacetylase (HDAC) dependent, and MBD4 directly binds to Sin3A and HDAC1 at three central regions that overlap transcriptional repression domains. Furthermore, a chromatin immunoprecipitation assay clearly shows that MBD4 binds to hypermethylated promoters of the p16(INK4a) and hMLH1 genes. These results suggest that MBD4 is one of the essential components involved in epigenetic silencing in cancer and its repair activity is necessary for the maintenance of hypermethylated promoters.