Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
Sci Adv. 2019 Jul 3;5(7):eaax2887. doi: 10.1126/sciadv.aax2887. eCollection 2019 Jul.
Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67's interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: (catalytic antagonist of Polycomb; official gene name: ). We map inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As expression is regulated through DNA methylation/demethylation, we propose as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.
通过对与子宫内膜间质肉瘤相关的融合蛋白的生化特征分析，我们鉴定出 JAZF1 是 NuA4 乙酰转移酶复合物的一个新亚基，CXORF67 是多梳抑制复合物 2（PRC2）的一个亚基。由于 CXORF67 与 PRC2 的相互作用导致 PRC2 依赖性 H3K27me2/3 沉积减少，我们为此基因提出了一个新的名称：（多梳抑制复合物 2 的催化拮抗剂；官方基因名称：）。我们将抑制功能定位到一个短的高度保守区域，并确定了一个单一的蛋氨酸残基，对于降低 H3K27me2/3 水平是必需的。值得注意的是，这个关键蛋氨酸周围的氨基酸序列类似于在高级别小儿神经胶质瘤中发现的致癌性组蛋白 H3 赖氨酸到蛋氨酸（H3K27M）突变。由于 表达受 DNA 甲基化/去甲基化的调控，我们提出 作为 DNA 甲基化和 PRC2 活性之间的潜在对话者。我们提出这样一种可能性，即类似的调控机制可能存在于其他甲基转移酶复合物中，如 Trithorax/COMPASS。
