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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由H3F3A和H3F3B两个基因编码。采用DNA全基因组测序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 variants play an important regulatory role in basic cellular processes such as gene expression. Humans have five H3 variants, H3.1, H3.2, H3.3, centromere-specific CENP-A, and testis-specific H3t. Human H3.3 is encoded by both H3F3A and H3F3B genes. High-frequency H3F3A mutations were identified using DNA genome-wide sequencing in pediatric high-grade gliomas such as glioblastoma (GBM) and diffuse intrinsic psoriatic gliomas (DIPG). More than 70% DIPG and 30% GBM carry the H3.3 K27M amino acid missense mutation (27th lysine replaced by methionine). H3.3 K27M inhibits polycomb inhibition of complex 2 (PRC2) activity and overall reduction of H3K27me3 content by interacting with the histone H3K27 methyltransferase EZH2 subunit. Therefore, the H3.3 K27M mutation remodels both the apparent modification status and the gene expression pattern to drive tumorigenesis. K27M mutation can be used as a molecular marker to better distinguish subtype of childhood glioma, but also as a specific and sensitive prognostic markers. Increasing H3K27 methylation by inhibiting histone demethylase, such as JMJD3 activity, may be an effective strategy for the treatment of K27M mutant glioma. This article reviews the histone variant H3.3 K27M in glioma mutation patterns, molecular mechanisms and clinical applications.