Takai Hiroki, Masuda Koji, Sato Tomohiro, Sakaguchi Yuriko, Suzuki Takeo, Suzuki Tsutomu, Koyama-Nasu Ryo, Nasu-Nishimura Yukiko, Katou Yuki, Ogawa Haruo, Morishita Yasuyuki, Kozuka-Hata Hiroko, Oyama Masaaki, Todo Tomoki, Ino Yasushi, Mukasa Akitake, Saito Nobuhito, Toyoshima Chikashi, Shirahige Katsuhiko, Akiyama Tetsu
Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Cell Rep. 2014 Oct 9;9(1):48-60. doi: 10.1016/j.celrep.2014.08.071. Epub 2014 Oct 2.
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 cancer-related genes.
癌症的发展不仅由基因突变驱动，还由表观遗传改变驱动。在此，我们表明胶质母细胞瘤细胞的致瘤性需要TET1介导的5-羟甲基胞嘧啶（5hmC）的产生。此外，我们证明PRMT1的染色质靶点（CHTOP）与5hmC结合。我们发现CHTOP与一种称为甲基osome的精氨酸甲基转移酶复合物相关，并且这促进了PRMT1介导的参与胶质母细胞瘤发生的基因（包括EGFR、AKT3、CDK6、CCND2和BRAF）中组蛋白H4的精氨酸3（H4R3）的甲基化。此外，我们发现CHTOP和PRMT1对于这些基因的表达至关重要，并且CHTOP是胶质母细胞瘤细胞致瘤性所必需的。这些结果表明，5hmC通过将CHTOP-甲基osome复合物募集到染色体上的选择性位点，在那里它使H4R3甲基化并激活癌症相关基因的转录，从而在胶质母细胞瘤发生中起关键作用。
