Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development
Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development
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DOI：
10.1101/gad.194101
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发表时间：
2001-03-15
影响因子：
10.5
通讯作者：
Bird, A
中科院分区：
文献类型：
--
作者：
Hendrich, B;Guy, J;Bird, A
MBD2 和 MBD3 是密切相关的蛋白质，具有共有的甲基 CpG 结合域。 MBD2 是一种转录抑制因子，可特异性结合甲基化 DNA，是 MeCP1 蛋白复合物的组成部分。相比之下，MBD3 无法结合小鼠细胞中的甲基化 DNA，并且是 Mi-2/NuRD 辅阻遏物复合物的组成部分。我们通过基因靶向表明，这两种蛋白在小鼠中并不是功能冗余的，因为 Mbd3(-/-) 小鼠在早期胚胎发生过程中死亡，而 Mbd2(-/-) 小鼠则存活且具有生育能力。然而，Mbd2(-/-)小鼠的母性行为是有缺陷的，并且在分子水平上，Mbd2(-/-)小鼠缺乏MeCP1的成分。 Mbd2突变细胞无法完全沉默外源甲基化模板的转录，但未检测到内源印记基因或逆转录病毒序列的不当激活。尽管存在差异，Mbd3 和 Mbd2 在遗传上相互作用，表明存在功能关系。遗传和生化数据共同支持这样的观点：MBD3 是 Mi-2/NuRD 辅阻遏物复合物的关键组成部分，而 MBD2 可能是可以将该复合物募集至 DNA 的几个因素之一。
MBD2 and MBD3 are closely related proteins with consensus methyl-CpG binding domains. MBD2 is a transcriptional repressor that specifically binds to methylated DNA and is a component of the MeCP1 protein complex. In contrast, MBD3 fails to bind methylated DNA in murine cells, and is a component of the Mi-2/NuRD corepressor complex. We show by gene targeting that the two proteins are not functionally redundant in mice, as Mbd3(-/-) mice die during early embryogenesis, whereas Mbd2(-/-) mice are viable and fertile. Maternal behavior of Mbd2(-/-) mice is however defective and, at the molecular level, Mbd2(-/-) mice lack a component of MeCP1. Mbd2-mutant cells fail to fully silence transcription from exogenous methylated templates, but inappropriate activation of endogenous imprinted genes or retroviral sequences was not detected. Despite their differences, Mbd3 and Mbd2 interact genetically suggesting a functional relationship. Genetic and biochemical data together favor the view that MBD3 is a key component of the Mi-2/NuRD corepressor complex, whereas MBD2 may be one of several factors that can recruit this complex to DNA.