Sampath Srihari C, Marazzi Ivan, Yap Kyoko L, Sampath Srinath C, Krutchinsky Andrew N, Mecklenbräuker Ingrid, Viale Agnes, Rudensky Eugene, Zhou Ming-Ming, Chait Brian T, Tarakhovsky Alexander
Laboratory of Lymphocyte Signaling, New York, NY 10021, USA.
Mol Cell. 2007 Aug 17;27(4):596-608. doi: 10.1016/j.molcel.2007.06.026.
Epigenetic gene silencing in eukaryotes is regulated in part by lysine methylation of the core histone proteins. While histone lysine methylation is known to control gene expression through the recruitment of modification-specific effector proteins, it remains unknown whether nonhistone chromatin proteins are targets for similar modification-recognition systems. Here we show that the histone H3 methyltransferase G9a contains a conserved methylation motif with marked sequence similarity to H3 itself. As with methylation of H3 lysine 9, autocatalytic G9a methylation is necessary and sufficient to mediate in vivo interaction with the epigenetic regulator heterochromatin protein 1 (HP1), and this methyl-dependent interaction can be reversed by adjacent G9a phosphorylation. NMR analysis indicates that the HP1 chromodomain recognizes methyl-G9a through a binding mode similar to that used in recognition of methyl-H3K9, demonstrating that the chromodomain functions as a generalized methyl-lysine binding module. These data reveal histone-like modification cassettes - or "histone mimics" - as a distinct class of nonhistone methylation targets and directly extend the principles of the histone code to the regulation of nonhistone proteins.
真核生物中的表观遗传基因沉默部分受核心组蛋白的赖氨酸甲基化调控。虽然已知组蛋白赖氨酸甲基化通过招募修饰特异性效应蛋白来控制基因表达，但非组蛋白染色质蛋白是否是类似修饰识别系统的靶点仍不清楚。在此，我们表明组蛋白H3甲基转移酶G9a含有一个保守的甲基化基序，与H3本身具有显著的序列相似性。与H3赖氨酸9的甲基化一样，自催化的G9a甲基化对于介导与表观遗传调节因子异染色质蛋白1（HP1）的体内相互作用是必要且充分的，并且这种甲基依赖性相互作用可被相邻的G9a磷酸化逆转。核磁共振分析表明，HP1的色域通过与识别甲基-H3K9相似的结合模式识别甲基-G9a，这表明色域作为一种通用的甲基赖氨酸结合模块发挥作用。这些数据揭示了组蛋白样修饰盒——或“组蛋白模拟物”——作为一类独特的非组蛋白甲基化靶点，并直接将组蛋白密码的原理扩展到非组蛋白的调控。
