Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas
Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas
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DOI：
10.1016/j.ccr.2013.10.006
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发表时间：
2013-11-11
期刊：
影响因子：
50.3
通讯作者：
Pfister, Stefan M.
中科院分区：
文献类型：
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作者：
Bender, Sebastian;Tang, Yujie;Pfister, Stefan M.
组蛋白变体H3.3中的两个复发突变K27M和G34R/V最近在50%的pHGGs中被发现。这两种突变定义了临床和生物学上不同的pHGGs亚群。在这里，我们进一步了解了K27M突变体H3.3的显性负作用，导致抑制组蛋白标记H3K27me3的全局减少。我们证明，这是由PRC2复合物异常募集到K27M突变体H3.3和酶抑制h3k27me3甲基转移酶EZH2引起的。通过对初级pHGGs进行染色质免疫沉淀、下一代测序和全基因组亚硫酸氢盐测序，我们发现H3K27me3水平降低和DNA低甲基化协同作用，激活了K27M突变型pHGGs的基因表达。
Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in similar to 50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.