The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression
The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression
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DOI：
10.1101/gad.217778.113
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发表时间：
2013-05-01
影响因子：
10.5
通讯作者：
Zhang, Zhiguo
中科院分区：
文献类型：
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作者：
Chan, Kui-Ming;Fang, Dong;Zhang, Zhiguo
近期研究在60%的高级别儿童胶质瘤病例中，在编码组蛋白H3变体H3.3的两个基因之一的H3F3A的一个等位基因上发现了赖氨酸27到甲硫氨酸（K27M）突变。这组患者确诊后的中位生存期约为1年。在此我们表明，由于H3.3K27M突变等位基因的表达，H3.3K27M患者样本中H3K27二甲基化和三甲基化（H3K27me2和H3K27me3）水平在整体上降低。值得注意的是，我们还观察到在H3.3K27M患者细胞中，染色质上的H3K27me3和Ezh2（H3K27甲基转移酶的催化亚基）在数百个基因位点局部显著增加。此外，基因启动子上H3K27me3和Ezh2的增加改变了与各种癌症通路相关的基因的表达。这些结果表明H3.3K27M突变重新编程了表观遗传景观和基因表达，这可能驱动肿瘤发生。
Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is similar to 1 yr. Here we show that the levels of H3K27 di-and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.