Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.
Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.
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DOI：
10.1126/science.aac7272
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发表时间：
2016-05-13
期刊：
影响因子：
--
通讯作者：
Lewis PW
中科院分区：
文献类型：
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作者：
Lu C;Jain SU;Hoelper D;Bechet D;Molden RC;Ran L;Murphy D;Venneti S;Hameed M;Pawel BR;Wunder JS;Dickson BC;Lundgren SM;Jani KS;De Jay N;Papillon-Cavanagh S;Andrulis IL;Sawyer SL;Grynspan D;Turcotte RE;Nadaf J;Fahiminiyah S;Muir TW;Majewski J;Thompson CB;Chi P;Garcia BA;Allis CD;Jabado N;Lewis PW
据报道，几种类型的儿科癌症在组蛋白H3中含有高频率的错义突变，但潜在的致癌机制仍然缺乏特征。在这里，我们报告说，H3赖氨酸36甲硫氨酸（H3 K36 M）突变损害间充质祖细胞的分化，并在体内产生未分化肉瘤。H3 K36 M突变核小体抑制几种H3 K36甲基转移酶的酶活性。耗尽H3 K36甲基转移酶，或表达类似地抑制H3 K36甲基化的H3 K36 I突变体，足以对H3 K36 M突变进行表型复制。在H3 K36甲基化丧失后，H3 K27甲基化的全基因组增益导致Polycomb抑制复合物1的重新分布和已知阻断间充质分化的其靶基因的去抑制。我们的研究结果反映在人类未分化肉瘤中，其中发现了H3.1中的新型K36 M/I突变。
Several types of pediatric cancers reportedly contain high frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here, we report that the H3 lysine 36 to methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. Following the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of Polycomb Repressive Complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas where novel K36M/I mutations in H3.1 are identified.