A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells.
A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells.
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DOI：
10.1038/nchembio.599
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发表时间：
2011-07-10
影响因子：
14.8
通讯作者：
Jin, Jian
中科院分区：
文献类型：
--
作者：
Vedadi, Masoud;Barsyte-Lovejoy, Dalia;Liu, Feng;Rival-Gervier, Sylvie;Allali-Hassani, Abdellah;Labrie, Viviane;Wigle, Tim J.;DiMaggio, Peter A.;Wasney, Gregory A.;Siarheyeva, Alena;Dong, Aiping;Tempel, Wolfram;Wang, Sun-Chong;Chen, Xin;Chau, Irene;Mangano, Thomas J.;Huang, Xi-ping;Simpson, Catherine D.;Pattenden, Samantha G.;Norris, Jacqueline L.;Kireev, Dmitri B.;Tripathy, Ashutosh;Edwards, Aled;Roth, Bryan L.;Janzen, William P.;Garcia, Benjamin A.;Petronis, Arturas;Ellis, James;Brown, Peter J.;Frye, Stephen V.;Arrowsmith, Cheryl H.;Jin, Jian
蛋白质赖氨酸甲基转移酶G9a和GLP通过组蛋白H3 （H3K9me2）上Lys9的二甲基化以及非组蛋白靶点的二甲基化来调节多种基因的转录抑制。在这里，我们报告了UNC0638的发现，这是一种G9a和GLP的抑制剂，对广泛的表观遗传和非表观遗传靶标具有优异的效力和选择性。UNC0638处理多种细胞系导致H3K9me2整体水平降低，与G9a和GLP的小发夹RNA敲低水平相当，且UNC0638的功能效力与毒性很好地分离。UNC0638显著降低了MCF7细胞的克隆原性，降低了已知g9a调控内源基因启动子上H3K9me2标记的丰度，并不成比例地影响了几个编码microrna的基因组位点。在小鼠胚胎干细胞中，UNC0638以浓度依赖的方式重新激活g9a沉默基因和逆转录病毒报告基因，而不促进分化。
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
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影响因子：
3.7
作者：
Kondo Y;Shen L;Ahmed S;Boumber Y;Sekido Y;Haddad BR;Issa JP
通讯作者：
Issa JP
影响因子：
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Pradhan, Sriharsa
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通讯作者：
Jenuwein, Thomas
影响因子：
7.3
作者：
Liu F;Chen X;Allali-Hassani A;Quinn AM;Wigle TJ;Wasney GA;Dong A;Senisterra G;Chau I;Siarheyeva A;Norris JL;Kireev DB;Jadhav A;Herold JM;Janzen WP;Arrowsmith CH;Frye SV;Brown PJ;Simeonov A;Vedadi M;Jin J
通讯作者：
Jin J