Klose Robert J, Yamane Kenichi, Bae Yangjin, Zhang Dianzheng, Erdjument-Bromage Hediye, Tempst Paul, Wong Jiemin, Zhang Yi
Howard Hughes Medical Institute, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.
Nature. 2006 Jul 20;442(7100):312-6. doi: 10.1038/nature04853. Epub 2006 May 28.
Post-translational modification of chromatin has profound effects on many biological processes including transcriptional regulation, heterochromatin organization, and X-chromosome inactivation. Recent studies indicate that methylation on specific histone lysine (K) residues participates in many of these processes. Lysine methylation occurs in three distinct states, having either one (me1), two (me2) or three (me3) methyl groups attached to the amine group of the lysine side chain. These differences in modification state have an important role in defining how methylated chromatin is recognized and interpreted. Until recently, histone lysine methylation was considered a stable modification, but the identification of histone demethylase enzymes has demonstrated the reversibility of this epigenetic mark. So far, all characterized histone demethylases show enzymatic activity towards lysine residues modified in the me1 or me2 state, leaving open the possibility that me3 constitutes an irreversible modification. Here we demonstrate that JHDM3A (jumonji C (JmjC)-domain-containing histone demethylase 3A; also known as JMJD2A) is capable of removing the me3 group from modified H3 lysine 9 (H3K9) and H3 lysine 36 (H3K36). Overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin, indicating a role for JHDM3A in antagonizing methylated H3K9 nucleated events. siRNA-mediated knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of a JHDM3A target gene, ASCL2, indicating that JHDM3A may function in euchromatin to remove histone methylation marks that are associated with active transcription.
染色质的翻译后修饰对包括转录调控、异染色质组织和X染色体失活在内的许多生物学过程具有深远影响。最近的研究表明，特定组蛋白赖氨酸（K）残基上的甲基化参与了其中许多过程。赖氨酸甲基化以三种不同状态发生，赖氨酸侧链的胺基上分别连接有一个（me1）、两个（me2）或三个（me3）甲基基团。这些修饰状态的差异在定义甲基化染色质如何被识别和解读方面起着重要作用。直到最近，组蛋白赖氨酸甲基化还被认为是一种稳定的修饰，但组蛋白去甲基化酶的鉴定证明了这种表观遗传标记的可逆性。到目前为止，所有已表征的组蛋白去甲基化酶都显示出对处于me1或me2状态修饰的赖氨酸残基具有酶活性，这使得me3构成不可逆修饰的可能性仍然存在。在这里，我们证明JHDM——含Jumonji C（JmjC）结构域的组蛋白去甲基化酶3A（也称为JMJD2A）能够从修饰的H3赖氨酸9（H3K9）和H3赖氨酸36（H3K36）上去除me3基团。JHDM3A的过表达消除了异染色质蛋白1（HP1）向异染色质的募集，表明JHDM3A在拮抗甲基化H3K9引发的事件中发挥作用。siRNA介导的JHDM3A敲低导致H3K9甲基化水平升高以及JHDM3A靶基因ASCL2的上调，表明JHDM3A可能在常染色质中发挥作用，去除与活跃转录相关的组蛋白甲基化标记。
