H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
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DOI：
10.1038/s41467-019-09140-x
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发表时间：
2019-03-19
影响因子：
16.6
通讯作者：
Majewski, Jacek
中科院分区：
文献类型：
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作者：
Harutyunyan, Ashot S.;Krug, Brian;Majewski, Jacek
组蛋白3基因（H3 K27 M）中的Lys-27-Met突变是致命胶质瘤亚组的特征，并降低了全基因组H3 K27三甲基化。在这里，我们使用原代H3 K27 M肿瘤细胞系和同基因CRISPR编辑的对照来评估H3 K27 M在体外和体内的作用。我们发现，尽管H3 K27 me 3和H3 K27 me 2通常由PRC 2在广泛区域沉积，但它们的沉积在H3.3K27M细胞中严重减少。H3 K27 me 3不能从大的未甲基化的CpG岛扩散，而H3 K27 me 2可以沉积在这些PRC 2高亲和力位点之外，但达到与野生型细胞中的H3 K27 me 3沉积相对应的水平。我们的研究结果表明，PRC 2在染色质上的募集和繁殖似乎不受K27 M的影响，K27 M主要损害其催化的抑制性标记的传播，特别是H3 K27 me 3。全基因组H3 K27 me 3和Met沉积的丢失具有有限的转录组学后果，优先影响调节神经发生的低表达基因。去除H3 K27 M恢复H3 K27 me 2/me 3扩散，损害细胞增殖，并完全消除它们在小鼠中形成肿瘤的能力。
Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and met deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.