Department of Biomolecular Chemistry, School of Medicine and Public Health and Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI, 53715, USA.
Department of Biochemistry and Biophysics, and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2019 May 13;10(1):2146. doi: 10.1038/s41467-019-09981-6.
Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.
后颅窝型 A （PFA）室管膜瘤表现出极低的 H3K27 甲基化，并表达高水平的 EZHIP（EZH2 抑制因子同源蛋白，也称为 CXORF67）。在这里，我们发现 EZHIP 中的一个保守序列在体外和体内都是抑制 PRC2 催化活性所必需和充分的。EZHIP 以类似于 H3 K27M 癌组蛋白的机制直接与 EZH2 亚基的活性位点结合。此外，细胞中 H3 K27M 或 EZHIP 的表达促进相似的染色质特征：广泛的 H3K27me3 结构域丢失，但 CpG 岛保留 H3K27me3。我们发现 H3K27me3 介导的 PRC2 变构激活大大增加了 EZHIP 和 H3 K27M 的抑制潜力，为解释观察到的 H3K27me3 扩散在肿瘤中的缺失提供了一种机制。我们的数据表明，部分 PFA 室管膜瘤和 DIPG 是由肽基 PRC2 抑制剂、癌组蛋白 K27M 和 EZHIP“癌组蛋白模拟物”的作用驱动的，这些抑制剂失调基因沉默以促进肿瘤发生。
