Tri-methylation of ATF7IP by G9a/GLP recruits the chromodomain protein MPP8.
Tri-methylation of ATF7IP by G9a/GLP recruits the chromodomain protein MPP8.
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DOI：
10.1186/s13072-018-0231-z
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发表时间：
2018-10-04
影响因子：
3.9
通讯作者：
Shinkai Y
中科院分区：
文献类型：
--
作者：
Tsusaka T;Kikuchi M;Shimazu T;Suzuki T;Sohtome Y;Akakabe M;Sodeoka M;Dohmae N;Umehara T;Shinkai Y
G9 a和相关酶GLP最初被鉴定为组蛋白赖氨酸甲基转移酶，然后显示也甲基化几种其他非组蛋白蛋白。在这里，我们进行了全面的筛选，以确定它们在小鼠胚胎干细胞（mESC）中的底物。我们鉴定了59种蛋白质，包括组蛋白和其他已知底物。其中一种已鉴定的底物，即转录因子7相互作用蛋白1（ATF 7IP），在组蛋白H3赖氨酸9（H3 K9）样模拟物处被G9 a/GLP复合物三甲基化，尽管该复合物主要在细胞中引入H3 K9和DNA连接酶1（LIG 1）K126上的二甲基化。G9 a的催化结构域对ATF 7IP上的二甲基化赖氨酸显示出比LIG 1更高的亲和力，这可能在细胞中产生不同底物的不同甲基化水平。此外，我们发现M期磷蛋白8（MPP 8），被称为H3 K9 me 3结合蛋白，识别甲基化的ATF 7IP通过其chromodomain。MPP 8也是人沉默中枢复合物的已知组分，其通过SETDB 1募集介导转基因的沉默，SETDB 1募集是ATF 7IP的结合配偶体。虽然ATF 7IP和SETDB 1之间的相互作用不依赖于ATF 7IP甲基化，但我们发现，在仅表达ATF 7IP的不可甲基化突变体的mESC中，SETDB 1/MPP 8介导的前病毒沉默的诱导被延迟。我们的研究结果为G9 a/GLP复合物靶向的非组蛋白底物中赖氨酸甲基化的作用提供了新的见解，并表明ATF 7IP甲基化在SETDB 1/MPP 8介导的转基因沉默中的潜在功能。本文的在线版本（10.1186/s13072-018-0231-z）包含补充材料，可供授权用户使用。
G9a and the related enzyme GLP were originally identified as histone lysine methyltransferases and then shown to also methylate several other non-histone proteins. Here, we performed a comprehensive screen to identify their substrates in mouse embryonic stem cells (mESCs). We identified 59 proteins, including histones and other known substrates. One of the identified substrates, activating transcriptional factor 7-interacting protein 1 (ATF7IP), is tri-methylated at a histone H3 lysine 9 (H3K9)-like mimic by the G9a/GLP complex, although this complex mainly introduces di-methylation on H3K9 and DNA ligase 1 (LIG1) K126 in cells. The catalytic domain of G9a showed a higher affinity for di-methylated lysine on ATF7IP than LIG1, which may create different methylation levels of different substrates in cells. Furthermore, we found that M-phase phosphoprotein 8 (MPP8), known as a H3K9me3-binding protein, recognizes methylated ATF7IP via its chromodomain. MPP8 is also a known component of the human silencing hub complex that mediates silencing of transgenes via SETDB1 recruitment, which is a binding partner of ATF7IP. Although the interaction between ATF7IP and SETDB1 does not depend on ATF7IP methylation, we found that induction of SETDB1/MPP8-mediated reporter-provirus silencing is delayed in mESCs expressing only an un-methylatable mutant of ATF7IP. Our findings provide new insights into the roles of lysine methylation in non-histone substrates which are targeted by the G9a/GLP complex and suggest a potential function of ATF7IP methylation in SETDB1/MPP8-mediated transgene silencing. The online version of this article (10.1186/s13072-018-0231-z) contains supplementary material, which is available to authorized users.
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影响因子：
7
作者：
Fukuda K;Okuda A;Yusa K;Shinkai Y
通讯作者：
Shinkai Y
影响因子：
5.3
作者：
O'Carroll, D;Scherthan, H;Jenuwein, T
通讯作者：
Jenuwein, T
DOI：
10.1023/b:jsfg.0000029204.57846.7d
发表时间：
2004-01-01
期刊：
Journal of Structural and Functional Genomics
影响因子：
--
作者：
Kigawa, Takanori;Yabuki, Takashi;Yokoyama, Shigeyuki
通讯作者：
Yokoyama, Shigeyuki
影响因子：
16.8
作者：
Metzger, Eric;Willmann, Dominica;Schuele, Roland
通讯作者：
Schuele, Roland
影响因子：
9.2
作者：
Lehnertz, B;Ueda, Y;Peters, AHFM
通讯作者：
Peters, AHFM