Kuzmichev Andrei, Jenuwein Thomas, Tempst Paul, Reinberg Danny
Robert Wood Johnson Medical School, Howard Hughes Medical Institute and Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
Mol Cell. 2004 Apr 23;14(2):183-93. doi: 10.1016/s1097-2765(04)00185-6.
Human Enhancer of Zeste homolog (Ezh2) is a histone lysine methyltransferase (HKMT) associated with transcriptional repression. Ezh2 is present in several distinct complexes, one of which, PRC2, we characterized previously. Here we report an additional Ezh2 complex, PRC3. We show that the Ezh2 complexes exhibit differential targeting of specific histones for lysine methylation dependent upon the context of the histone substrates. This differential targeting is a function of the associated Eed protein within each complex. We found that Eed protein is present in four isoforms, which represent alternate translation start site usage from the same mRNA. These Eed isoforms selectively associate with distinct Ezh2-containing complexes with resultant differential targeting of their associated HKMT activity toward histone H3-K27 or histone H1-K26. Our data provide evidence for a novel mechanism regulating the substrate specificity of a chromatin-modifying enzyme through disparate translational products of a regulatory subunit.
人类Zeste同源增强子（Ezh2）是一种与转录抑制相关的组蛋白赖氨酸甲基转移酶（HKMT）。Ezh2存在于几种不同的复合物中，其中一种复合物PRC2，我们之前已对其进行了表征。在此我们报告另一种Ezh2复合物PRC3。我们表明，Ezh2复合物根据组蛋白底物的背景情况，对特定组蛋白赖氨酸甲基化表现出不同的靶向作用。这种差异靶向是每个复合物中相关Eed蛋白的一种功能。我们发现Eed蛋白存在四种异构体，它们代表来自同一mRNA的不同翻译起始位点的使用情况。这些Eed异构体选择性地与不同的含Ezh2复合物结合，从而导致其相关HKMT活性对组蛋白H3-K27或组蛋白H1-K26的靶向作用不同。我们的数据为通过调节亚基的不同翻译产物来调控染色质修饰酶底物特异性的新机制提供了证据。
