Department of Biochemistry and Molecular Biology, Epigenomic Developmental Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Cell Cycle. 2013 Aug 15;12(16):2546-52. doi: 10.4161/cc.25625. Epub 2013 Jul 10.
Glioblastoma (GBM) is the most aggressive primary brain tumor in human. Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1). The two histone H3 mutations are mutually exclusive and give rise to tumors in different brain compartments. Recently, we and others have shown that the histone H3 K27M mutation specifically altered the di- and tri-methylation of endogenous histone H3 at Lys27. Genome-wide studies using ChIP-seq on H3.3K27M patient samples indicate a global reduction of H3K27me3 on chromatin. Remarkably, we also found a dramatic enrichment of H3K27me3 and EZH2 (the catalytic subunit H3K27 methyltransferase) at hundreds of gene loci in H3.3K27M patient cells. Here, we discuss potential mechanisms whereby H3K27me3 is enriched at chromatin loci in cells expressing the H3.3K27M mutation and report effects of Lys-to-Met mutations of other well-studied lysine residues of histone H3.1/H3.3 and H4 on the corresponding endogenous lysine methylation. We suggest that mutation(s) on histones may be found in a variety of human diseases, and the expression of mutant histones may help to address the function of histone lysine methylation and possibly other modifications in mammalian cells.
胶质母细胞瘤（GBM）是人类中最具侵袭性的原发性脑肿瘤。最近对高级别儿童 GBM 的研究在编码组蛋白 H3 的基因中鉴定出两种反复出现的突变（K27M 和 G34R/V）（H3.3 的 H3F3A 和 H3.1 的 HIST1H3B）。这两种组蛋白 H3 突变是相互排斥的，导致不同脑区的肿瘤。最近，我们和其他人已经表明，组蛋白 H3 K27M 突变特异性改变了内源性组蛋白 H3 在赖氨酸 27 处的二甲基化和三甲基化。使用 H3.3K27M 患者样本的 ChIP-seq 进行的全基因组研究表明染色质上 H3K27me3 的整体减少。值得注意的是，我们还在 H3.3K27M 患者细胞中数百个基因座发现了 H3K27me3 和 EZH2（H3K27 甲基转移酶的催化亚基）的显著富集。在这里，我们讨论了在表达 H3.3K27M 突变的细胞中染色质位点上 H3K27me3 富集的潜在机制，并报告了组蛋白 H3.1/H3.3 和 H4 的其他研究充分的赖氨酸残基的 Lys-to-Met 突变对相应的内源性赖氨酸甲基化的影响。我们认为，组蛋白上的突变可能存在于多种人类疾病中，并且突变组蛋白的表达可能有助于解决组蛋白赖氨酸甲基化和哺乳动物细胞中可能的其他修饰的功能。
