组蛋白变体H3.3 L27M突变与胶质瘤发生

组蛋白变体在基因表达等基本细胞过程中发挥重要调节功能。人类有5种H3变体，分别为H3.1、 H3.2、H3.3、着丝粒特异性CENP-A和睾丸特异性H3t。人H3.3有H3F3A和H3F3B两个基因编码。采用DNA全基因组测序的方法在儿童高级别胶质瘤如恶性胶质瘤（GBM）和弥漫性内在脑桥胶质瘤（DIPG）鉴定出高频的H3F3A突变。超过70%DIPG和30%GBM携带H3.3 K27M氨基酸错义突变（27位赖氨酸被甲硫氨酸代替）。H3.3 K27M通过与组蛋白H3K27甲基转移酶EZH2亚基相互作用而抑制多梳抑制复合物2（PRC2）活性并全面减少H3K27me3含量。因此H3.3 K27M突变重塑了表观修饰状态和基因表达模式，从而驱动肿瘤发生。K27M突变可作为分子标志物以更好区分儿童胶质瘤亚型，还可作为特异、敏感的预后标志物。通过抑制组蛋白去甲基化酶如JMJD3活性而增加H3K27甲基化可作为K27M突变胶质瘤治疗的有效策略。本文综述了组蛋白变体H3.3 K27M在胶质瘤中的突变模式、分子机制和临床应用。

Histone Variant H3.3 K27M Mutation in Glioma

Histone variants are key players in regulating fundamental cellular processes such as gene expression. In human, there are five H3 variants, H3.1, H3.2, H3.3, centromere specific histone CENP-A (centromere protein A) and testis specific histone H3t. Human H3.3 is encoded by two genes, H3F3A and H3F3B. Recurrent H3F3A mutations were identified with whole-genome sequencing of DNA in pediatric high-grade gliomas, such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG).There are over 70% of DIPG and 30% of GBM carrying K27M amino acid missense mutation (methionine replaces lysine 27) in histone variant H3.3. H3.3 K27M mutation can inhibit the enzymatic activity of the Polycomb repressive complex 2 through interaction with the H3K27 methyltransferase EZH2 subunit and globally reduce H3K27me3 levels. H3.3 K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis. K27M mutant can be used as a molecular marker to better distinguish pediatric gliomas subgroups. K27M mutant can also be used as a sensitive and specific prognostic marker for pediatric gliomas. It is a valid therapeutic strategy for treating K27M mutant glioma to increase H3K27 methylation by inhibiting H3K27 demethylase such as JMJD3. Here, we review the histone variant H3.3 H3K27 mutation pattern, molecular mechanism and clinical application in pediatric gliomas.