Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases
Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases
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DOI：
10.1073/pnas.0707292104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Ge, Kai
中科院分区：
文献类型：
--
作者：
Hong, SunHwa;Cho, Young-Wook;Ge, Kai
组蛋白的共价修饰，如乙酰化和甲基化，在基因表达调控中起着重要作用。组蛋白赖氨酸甲基化与基因激活和抑制有关，这取决于甲基化的特定赖氨酸（K）残基和甲基化状态（单甲基化、双甲基化或三甲基化）。组蛋白H3的K4、K9和K36上的甲基化已被证明是可逆的，并且可以通过位点特异性甲基化酶去除。然而，拮抗组蛋白H3（H3K27）的K27甲基化的酶，胚胎干细胞维持，Polycomb介导的基因沉默和X染色体失活的重要表观遗传标记一直难以捉摸。在这里，我们展示了含有JmjC结构域的蛋白UTX（普遍转录的tetratricopeparticle重复序列，X染色体），以及相关的含有3）的JMJID3 aumonji结构域，在体外特异性地去除H3K27上的甲基标记。此外，UTX的氯甲基化酶活性需要催化活性的JmjC结构域。最后，UTX和JMJD3的过表达导致细胞中H3K27上的二甲基化和三甲基化减少，表明UTX和JMJD3在体内可作为H3K27甲基化酶起作用。将UTX和JMJID3鉴定为H3K27特异性甲基化酶提供了直接证据，表明与组蛋白H3的K4、K9和K36上的甲基化类似，H311K27上的甲基化也是可逆的，并且可以通过位点特异性组蛋白甲基转移酶和甲基化酶动态调节。
Covalent modifications of histones, such as acetylation and methylation, play important roles in the regulation of gene expression. Histone lysine methylation has been implicated in both gene activation and repression, depending on the specific lysine (K) residue that becomes methylated and the state of methylation (mono-, di-, or trimethylation). Methylation on K4, K9, and K36 of histone H3 has been shown to be reversible and can be removed by site-specific clemethylases. However, the enzymes that antagonize methylation on K27 of histone H3 (H3K27), an epigenetic mark important for embryonic stem cell maintenance, Polycombmediated gene silencing, and X chromosome inactivation have been elusive. Here we show the JmjC domain-containing protein UTX (ubiquitously transcribed tetratricopepticle repeat, X chromosome), as well as the related JMJID3 aumonji domain containing 3), specifically removes methyl marks on H3K27 in vitro. Further, the clemethylase activity of UTX requires a catalytically active JmjC domain. Finally, overexpression of UTX and JMJD3 leads to reduced di- and trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may function as H3K27 clemethylases in vivo. The identification of UTX and JMJID3 as H3K27-specific clemethylases provides direct evidence to indicate that similar to methylation on K4, K9, and K36 of histone H3, methylation on H311 < 27 is also reversible and can be dynamically regulated by site-specif ic histone methyltransferases and clemethylases.