Hyllus Dawin, Stein Claudia, Schnabel Kristin, Schiltz Emile, Imhof Axel, Dou Yali, Hsieh James, Bauer Uta-Maria
Institute of Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, 35032 Marburg, Germany.
Genes Dev. 2007 Dec 15;21(24):3369-80. doi: 10.1101/gad.447007.
The arginine methyltransferase PRMT6 (protein arginine methyltransferase 6) has been shown recently to regulate DNA repair and gene expression. As arginine methylation of histones is an important mechanism in transcriptional regulation, we asked whether PRMT6 possesses activity toward histones. We show here that PRMT6 methylates histone H3 at R2 and histones H4/H2A at R3 in vitro. Overexpression and knockdown analysis identify PRMT6 as the major H3 R2 methyltransferase in vivo. We find that H3 R2 methylation inhibits H3 K4 trimethylation and recruitment of WDR5, a subunit of the MLL (mixed lineage leukemia) K4 methyltransferase complex, to histone H3 in vitro. Upon PRMT6 overexpression, transcription of Hox genes and Myc-dependent genes, both well-known targets of H3 K4 trimethylation, decreases. This transcriptional repression coincides with enhanced occurrence of H3 R2 methylation and PRMT6 as well as reduced levels of H3 K4 trimethylation and MLL1/WDR5 recruitment at the HoxA2 gene. Upon retinoic acid-induced transcriptional activation of HoxA2 in a cell model of neuronal differentiation, PRMT6 recruitment and H3 R2 methylation are diminished and H3 K4 trimethylation increases at the gene. Our findings identify PRMT6 as the mammalian methyltransferase for H3 R2 and establish the enzyme as a crucial negative regulator of H3 K4 trimethylation and transcriptional activation.
精氨酸甲基转移酶PRMT6（蛋白质精氨酸甲基转移酶6）最近已被证明可调节DNA修复和基因表达。由于组蛋白的精氨酸甲基化是转录调控中的一个重要机制，我们不禁要问PRMT6是否对组蛋白具有活性。我们在此表明，PRMT6在体外可使组蛋白H3的R2位点以及组蛋白H4/H2A的R3位点发生甲基化。过表达和敲低分析确定PRMT6是体内主要的H3 R2甲基转移酶。我们发现，H3 R2甲基化在体外可抑制H3 K4三甲基化以及WDR5（混合谱系白血病K4甲基转移酶复合体的一个亚基）与组蛋白H3的结合。PRMT6过表达时，Hox基因和Myc依赖性基因（二者均为H3 K4三甲基化的著名靶点）的转录会减少。这种转录抑制与HoxA2基因处H3 R2甲基化和PRMT6的出现增加以及H3 K4三甲基化水平和MLL1/WDR5结合的降低相一致。在神经元分化细胞模型中，视黄酸诱导HoxA2转录激活时，该基因处PRMT6的结合和H3 R2甲基化减少，而H3 K4三甲基化增加。我们的研究结果确定PRMT6为H3 R2的哺乳动物甲基转移酶，并证实该酶是H3 K4三甲基化和转录激活的关键负调节因子。
