DNMT3L将组蛋白H3的未甲基化的赖氨酸4连接到DNA的去甲基化

DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.

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|核心内容：

哺乳动物利用DNA甲基化使反转录转座子和印记基因遗传沉默，并使雌性X染色体失活。

配子发生过程中DNA甲基化模式的建立在一定程度上依赖于DNMT3L，这是一种酶失活的调节因子，与DNA甲基转移酶DNMT3a和Dnmt3b序列相关。

经质谱鉴定，与内源性Dnmt3L基因表位标记等位基因产物在体内相互作用的主要蛋白为DNMT3A2、Dnmt3b和4个核心组蛋白。

肽相互作用分析表明，DNMT3L与组蛋白H3的极端氨基末端发生特异性相互作用，这种相互作用被组蛋白H3的赖氨酸4位甲基化强烈抑制，但对其他位点的修饰不敏感。

人DNMT3L的结晶学研究表明，该蛋白含有一个羧基末端甲基转移酶样结构域和一个富含半胱氨酸的N末端结构域。

DNMT3L与组蛋白H3尾部的共结晶表明，DNMT3L的尾部与DNMT3L富含半胱氨酸的结构域结合，结合位点上的关键残基的取代消除了H3Tail与DNMT3L的相互作用。

这些数据表明，DNMT3L识别赖氨酸4处未甲基化的组蛋白H3尾巴，并通过招募或激活DNMT3A2来诱导DNA从头甲基化。

原文摘要：

Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.

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参考文献：10.1038/nature05987

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