H3K27M 在神经胶质瘤中导致 H3K27 甲基化的一步降低，并在 H3K36 甲基化的限制内减少扩散。

H3K27M in Gliomas Causes a One-Step Decrease in H3K27 Methylation and Reduced Spreading within the Constraints of H3K36 Methylation.

机构信息

Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada; The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.

Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.

出版信息

Cell Rep. 2020 Nov 17;33(7):108390. doi: 10.1016/j.celrep.2020.108390.

The discovery of H3K27M mutations in pediatric gliomas marked a new chapter in cancer epigenomics. Numerous studies have investigated the effect of this mutation on H3K27 trimethylation, but only recently have we started to realize its additional effects on the epigenome. Here, we use isogenic glioma H3K27M cell lines to investigate H3K27 methylation and its interaction with H3K36 and H3K9 modifications. We describe a "step down" effect of H3K27M on the distribution of H3K27 methylation: me3 is reduced to me2, me2 is reduced to me1, whereas H3K36me2/3 delineates the boundaries for the spread of H3K27me marks. We also observe a replacement of H3K27me2/3 silencing by H3K9me3. Using a computational simulation, we explain our observations by reduced effectiveness of PRC2 and constraints imposed on the deposition of H3K27me by antagonistic H3K36 modifications. Our work further elucidates the effects of H3K27M in gliomas as well as the general principles of deposition in H3K27 methylation.

H3K27M 突变在小儿神经胶质瘤中的发现标志着癌症表观基因组学的新篇章。许多研究已经调查了这种突变对 H3K27 三甲基化的影响，但直到最近我们才开始意识到它对表观基因组的额外影响。在这里，我们使用同基因神经胶质瘤 H3K27M 细胞系来研究 H3K27 甲基化及其与 H3K36 和 H3K9 修饰的相互作用。我们描述了 H3K27M 对 H3K27 甲基化分布的“逐步下降”效应：me3 减少到 me2，me2 减少到 me1，而 H3K36me2/3 描绘了 H3K27me 标记扩散的边界。我们还观察到 H3K27me2/3 沉默被 H3K9me3 取代。通过计算模拟，我们通过降低 PRC2 的有效性和拮抗 H3K36 修饰对 H3K27me 沉积的限制来解释我们的观察结果。我们的工作进一步阐明了 H3K27M 在神经胶质瘤中的作用以及 H3K27 甲基化沉积的一般原则。