Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada.
Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
Nat Commun. 2019 Mar 19;10(1):1262. doi: 10.1038/s41467-019-09140-x.
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 me2 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.
组蛋白 3 基因（H3K27M）中的 Lys-27-Met 突变特征是致命性神经胶质瘤的一个亚组，并降低全基因组 H3K27 三甲基化。在这里，我们使用原代 H3K27M 肿瘤系和同源 CRISPR 编辑对照来评估 H3K27M 在体外和体内的影响。我们发现，虽然 PRC2 通常在广泛的区域内沉积 H3K27me3 和 H3K27me2，但在 H3.3K27M 细胞中其沉积严重减少。H3K27me3 无法从大的未甲基化 CpG 岛传播，而 H3K27me2 可以在这些 PRC2 高亲和力位点之外沉积，但水平对应于野生型细胞中 H3K27me3 的沉积。我们的研究结果表明，PRC2 在染色质上的募集和传播似乎不受 K27M 的影响，K27M 主要损害其催化的抑制性标记的传播，尤其是 H3K27me3。全基因组丧失 H3K27me3 和 me2 沉积对转录组的影响有限，优先影响调节神经发生的低表达基因。去除 H3K27M 可恢复 H3K27me2/me3 的传播，损害细胞增殖，并完全消除其在小鼠中形成肿瘤的能力。
