Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro.
Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro.
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DOI：
10.1002/humu.22946
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发表时间：
2016-03
期刊：
影响因子：
3.9
通讯作者：
Gibson WT
中科院分区：
文献类型：
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作者：
Cohen AS;Yap DB;Lewis ME;Chijiwa C;Ramos-Arroyo MA;Tkachenko N;Milano V;Fradin M;McKinnon ML;Townsend KN;Xu J;Van Allen MI;Ross CJ;Dobyns WB;Weaver DD;Gibson WT
韦弗综合征是一种罕见的先天性疾病，其特征是全身性过度生长、大头畸形、特殊的面部特征、骨龄加速、智力残疾和对癌症的易感性。Zeste同源物2增强子（EZH2）中的从头突变已被证明会导致WS JZH2是一种组蛋白甲基转移酶，其充当多梳抑制复合物2（PRC2）的催化剂，以通过组蛋白H3（H3K27）上赖氨酸27的甲基化来维持基因抑制。已经报道了研究来自各种癌症的突变EZH2的组蛋白甲基转移酶活性的功能研究，而WS相关突变的特征仍然很差。为了研究EZH2在WS中的作用，我们使用人工组装的PRC2复合物进行了功能研究，该复合物含有突变的人EZH2，反映了WS患者预测的密码子变化。我们发现WS相关的氨基酸改变降低了EZH2在体外试验中的组蛋白甲基转移酶功能。我们的研究结果支持了这样的假设，即WS是由EZH2的组成突变引起的，EZH2改变了PRC2的组蛋白甲基转移酶功能。然而，不同EZH2变体的组蛋白甲基转移酶活性似乎与WS患者和EZH2中具有共同c.553G>C（p.Asp185His）多态性的个体之间的表型变异性没有直接相关性。
Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb‐repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS‐associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS‐associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.