Molecular coupling of DNA methylation and histone methylation.

Molecular coupling of DNA methylation and histone methylation.
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DOI:
10.2217/epi.10.44
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发表时间:
2010-10
期刊:
影响因子:
3.8
通讯作者:
Cheng X
Cheng X
中科院分区:
医学4区
文献类型:
--
作者:
Hashimoto H;Vertino PM;Cheng X

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DNA和组蛋白修饰的组合模式构成了表观遗传“密码”,其通过启用或限制基因组结构域的转录潜力来塑造基因表达模式。DNA甲基化与组蛋白修饰相关,特别是组蛋白H3赖氨酸4甲基化(H3 K4 me 0)的缺失和H3 K9甲基化的存在。本文重点介绍三个蛋白质结构域(ATRX-Dnmt 3-Dnmt 3L [ADD]、Cys-X-X-Cys [CXXC]和甲基-CpG结合结构域[MBD])以及结构域结构在哺乳动物细胞中连接组蛋白甲基化和DNA甲基化的机制中的功能意义。DNA甲基转移酶DNMT 3a及其辅助蛋白DNMT 3L含有H3 K4 me 0相互作用的ADD结构域,其将DNA甲基化反应与未修饰的H3 K4连接。H3 K4甲基转移酶MLL 1含有一个CpG相互作用的CXXC结构域,可以将H3 K4甲基化反应与未甲基化的DNA偶联。另一种H3 K4甲基转移酶SET 1虽然缺乏内在的CXXC结构域,但直接与含有相同结构域的辅助蛋白CFP 1相互作用。H3 K9甲基转移酶SETDB 1含有一个推定的MBD,它可能将H3 K4甲基化反应与甲基化DNA连接起来,或者可以通过与含有MBD的蛋白MBD 1相互作用来连接。最后,我们考虑了DNA甲基转移酶DNMT 1,其辅助蛋白UHRF 1及其相关蛋白的结构域结构,并提出了一种机制,通过该机制,DNA甲基化和组蛋白甲基化可以通过有丝分裂细胞分裂协调维持,允许传递亲本DNA和组蛋白甲基化模式复制到新复制的染色质。
The combinatorial pattern of DNA and histone modifications constitutes an epigenetic ‘code’ that shapes gene-expression patterns by enabling or restricting the transcriptional potential of genomic domains. DNA methylation is associated with histone modifications, particularly the absence of histone H3 lysine 4 methylation (H3K4me0) and the presence of H3K9 methylation. This article focuses on three protein domains (ATRX–Dnmt3–Dnmt3L [ADD], Cys–X–X–Cys [CXXC] and the methyl-CpG-binding domain [MBD]) and the functional implications of domain architecture in the mechanisms linking histone methylation and DNA methylation in mammalian cells. The DNA methyltransferase DNMT3a and its accessory protein DNMT3L contain a H3K4me0-interacting ADD domain that links the DNA methylation reaction with unmodified H3K4. The H3K4 methyltransferase MLL1 contains a CpG-interacting CXXC domain that may couple the H3K4 methylation reaction to unmethylated DNA. Another H3K4 methyltransferase, SET1, although lacking an intrinsic CXXC domain, interacts directly with an accessory protein CFP1 that contains the same domain. The H3K9 methyltransferase SETDB1 contains a putative MBD that potentially links the H3K4 methylation reaction to methylated DNA or may do so through the interaction with the MBD containing protein MBD1. Finally, we consider the domain structure of the DNA methyltransferase DNMT1, its accessory protein UHRF1 and their associated proteins, and propose a mechanism by which DNA methylation and histone methylation may be coordinately maintained through mitotic cell division, allowing for the transmission of parental DNA and for the histone methylation patterns to be copied to newly replicated chromatin.
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