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Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2020-11-03 , DOI: 10.1073/pnas.2006076117
Siddhant U. Jain 1 , Sima Khazaei 2, 3, 4 , Dylan M. Marchione 5, 6 , Stefan M. Lundgren 1 , Xiaoshi Wang 5, 6 , Daniel N. Weinberg 7 , Shriya Deshmukh 8 , Nikoleta Juretic 2, 3, 4 , Chao Lu 9 , C. David Allis 7 , Benjamin A. Garcia 5, 6 , Nada Jabado 2, 3, 4 , Peter W. Lewis 1
Affiliation  

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.



中文翻译:

组蛋白H3.3 G34突变促进异常PRC2活性并推动肿瘤进展[生化]

据报道,在编码组蛋白变体H3.3的基因中,高比例的儿科神经胶质瘤和骨肿瘤在34号甘氨酸处存在错义突变。我们发现这些H3.3 G34突变通过SETD2阻止组蛋白H3(H3K36)上赖氨酸36处的甲基化,而不是NSD1 / 2酶,直接改变了间充质干细胞的增强子染色质景观。由G34突变引起的H3K36甲基化的减少促进了含有SETD2活性的活性增强子上PRC2介导的H3K27me2 / 3的异常获得和H3K27ac的丧失。这种改变的组蛋白修饰谱促进了独特的基因表达谱,其支持体内增强的肿瘤发展。我们的发现反映在含G34W的骨巨细胞瘤中,其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,我们证明了H3.3 G34癌蛋白通过干扰SETD2介导的H3K36甲基化选择性地促进PRC2活性。我们提出,PRC2介导的细胞分化涉及的增强子沉默代表H3.3 G34突变驱动这些肿瘤的潜在机制。

更新日期:2020-11-04
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