5-Hydroxymethylcytosine Plays a Critical Role in Glioblastomagenesis by Recruiting the CHTOP-Methylosome Complex
5-Hydroxymethylcytosine Plays a Critical Role in Glioblastomagenesis by Recruiting the CHTOP-Methylosome Complex
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DOI：
10.1016/j.celrep.2014.08.071
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发表时间：
2014-10-09
期刊：
影响因子：
8.8
通讯作者：
Akiyama, Tetsu
中科院分区：
文献类型：
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作者：
Takai, Hiroki;Masuda, Koji;Akiyama, Tetsu
癌症的发展不仅由基因突变驱动，也由表观遗传变化驱动。在这里，我们证明了TET1介导的5-羟甲基胞嘧啶(5hmC)的产生是胶质母细胞瘤细胞致瘤性所必需的。此外，我们还证明了PRMT1(CHTOP)的染色质靶标与5hmC结合。我们发现CHTOP与精氨酸甲基转移酶复合体相关，这种复合体促进了PRMT1介导的组蛋白H4(H4R3)在组蛋白H4(H4R3)中的精氨酸3甲基化，这些基因包括EGFR、AKT3、CDK6、CCND2和BRAF。此外，我们发现CHTOP和PRMT1对于这些基因的表达是必不可少的，并且CHTOP对于胶质母细胞瘤细胞的致瘤性是必需的。这些结果表明，5hmC通过将CHTOP-羟甲基复合体招募到染色体上的选择性位置，在那里甲基化H4R3并激活癌症相关基因的转录，在胶质母细胞瘤的形成中发挥关键作用。
The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5-hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancerrelated genes.