Jain Siddhant U, Khazaei Sima, Marchione Dylan M, Lundgren Stefan M, Wang Xiaoshi, Weinberg Daniel N, Deshmukh Shriya, Juretic Nikoleta, Lu Chao, Allis C David, Garcia Benjamin A, Jabado Nada, Lewis Peter W
Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706.
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27354-27364. doi: 10.1073/pnas.2006076117. Epub 2020 Oct 16.
A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.
据报道，高比例的小儿胶质瘤和骨肿瘤在编码组蛋白变体H3.3的基因中，甘氨酸34位点存在错义突变。我们发现，这些H3.3 G34突变通过阻碍SETD2介导的组蛋白H3赖氨酸36（H3K36）甲基化，而非NSD1/2酶介导的甲基化，直接改变间充质干细胞的增强子染色质景观。G34突变导致的H3K36甲基化减少，促进了PRC2介导的H3K27me2/3异常增加，以及含有SETD2活性的活性增强子处H3K27ac的丢失。这种改变的组蛋白修饰谱促进了独特的基因表达谱，支持体内肿瘤发展增强。我们的发现也反映在含有G34W的骨巨细胞瘤中，患者来源的基质细胞表现出与早期成骨细胞分化相关的基因表达谱。总体而言，我们证明H3.3 G34癌组蛋白通过干扰SETD2介导的H3K36甲基化，选择性地促进PRC2活性。我们提出，PRC2介导的参与细胞分化的增强子沉默，是H3.3 G34突变驱动这些肿瘤的一种潜在机制。
