Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethylation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene repressor to an activator is unclear. Here, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcription machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2−EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is entirely sequestered. The EZH2 TAD can be unlocked by cancer-specific EZH2 phosphorylation events to undergo structural transitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The corresponding TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural context of the EZH2 TAD.

Enhancer of Zeste Homolog 2 (EZH2) 是 Polycomb Repressive Complex 2 (PRC2) 的催化亚基，它最少需要另外两个亚基 EED 和 SUZ12 来实现酶活性。传统上已知 EZH2 介导组蛋白 H3K27 三甲基化，这是沉默染色质的标志。新出现的证据表明，EZH2 还在与典型 PRC2 不同的背景下激活癌细胞中的基因表达。EZH2 从基因抑制子功能转变为激活子的分子机制尚不清楚。在这里，我们发现 EZH2 具有一个隐藏的、部分无序的反式激活结构域 (TAD)，能够与活性转录机制的组件相互作用，模仿原型酸性激活剂。EZH2 TAD 包含 SRM（刺激响应基序）和 SANT1（SWI3、ADA2、N-CoR 和 TFIIIB 1）区域，这些区域通常参与 H3K27 甲基化。EZH2−EED 二元复合物的晶体结构表明，EZH2 TAD 在非规范 PRC2 环境中介导蛋白质寡聚化，并且完全被隔离。EZH2 TAD 可以通过癌症特异性 EZH2 磷酸化事件解锁，以经历可能实现后续转录共激活因子结合的结构转变。EZH2 TAD 直接与转录共激活因子和组蛋白乙酰转移酶 p300 相互作用，并以 p300 依赖性方式激活细胞中的基因表达。相应的 TAD 也可能解释 EZH1（EZH2 的旁系同源物）的基因激活功能。已知在癌细胞中将 EZH2 异常转化为基因激活剂的不同激酶信号传导途径现在可以在 EZH2 TAD 的共同结构背景下进行理解。