Zhang Yanjun, Fang Dong
Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
Cell Death Dis. 2021 Mar 24;12(4):311. doi: 10.1038/s41419-021-03597-9.
The histone H3.3K36M mutation, identified in over 90% of chondroblastoma cases, reprograms the H3K36 methylation landscape and gene expression to promote tumorigenesis. However, it's still unclear how the H3K36M mutation preferentially occurs in the histone H3 variant H3.3 in chondroblastomas. Here, we report that H3.3K36M-, but not H3.1K36M-, mutant cells showed increased colony formation ability and differentiation defects. H3K36 methylations and enhancers were reprogrammed to different status in H3.3K36M- and H3.1K36M-mutant cells. The reprogramming of H3K36 methylation and enhancers was depended on the specific loci at which H3.3K36M and H3.1K36M were incorporated. Moreover, targeting H3K36M-mutant proteins to the chromatin inhibited the H3K36 methylation locally. Taken together, these results highlight the roles of the chromatic localization of H3.3K36M-mutant protein in the reprogramming of the epigenome and the subsequent induction of tumorigenesis, and shed light on the molecular mechanisms by which the H3K36M mutation mainly occurs in histone H3.3 in chondroblastomas.
在超过90%的软骨母细胞瘤病例中发现的组蛋白H3.3K36M突变，会重新编程H3K36甲基化格局和基因表达以促进肿瘤发生。然而，目前尚不清楚H3K36M突变如何在软骨母细胞瘤的组蛋白H3变体H3.3中优先发生。在此，我们报告H3.3K36M突变细胞（而非H3.1K36M突变细胞）显示出增加的集落形成能力和分化缺陷。H3K36甲基化和增强子在H3.3K36M和H3.1K36M突变细胞中被重新编程为不同状态。H3K36甲基化和增强子的重新编程取决于H3.3K36M和H3.1K36M整合的特定位点。此外，将H3K36M突变蛋白靶向染色质可局部抑制H3K36甲基化。综上所述，这些结果突出了H3.3K36M突变蛋白的染色质定位在表观基因组重编程及随后肿瘤发生诱导中的作用，并揭示了H3K36M突变主要在软骨母细胞瘤的组蛋白H3.3中发生的分子机制。
