Guccione Ernesto, Bassi Christian, Casadio Fabio, Martinato Francesca, Cesaroni Matteo, Schuchlautz Henning, Lüscher Bernhard, Amati Bruno
Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Milan 20139, Italy.
Nature. 2007 Oct 18;449(7164):933-7. doi: 10.1038/nature06166. Epub 2007 Sep 26.
Eukaryotic genomes are organized into active (euchromatic) and inactive (heterochromatic) chromatin domains. Post-translational modifications of histones (or 'marks') are key in defining these functional states, particularly in promoter regions. Mutual regulatory interactions between these marks--and the enzymes that catalyse them--contribute to the shaping of this epigenetic landscape, in a manner that remains to be fully elucidated. We previously observed that asymmetric di-methylation of histone H3 arginine 2 (H3R2me2a) counter-correlates with di- and tri- methylation of H3 lysine 4 (H3K4me2, H3K4me3) on human promoters. Here we show that the arginine methyltransferase PRMT6 catalyses H3R2 di-methylation in vitro and controls global levels of H3R2me2a in vivo. H3R2 methylation by PRMT6 was prevented by the presence of H3K4me3 on the H3 tail. Conversely, the H3R2me2a mark prevented methylation of H3K4 as well as binding to the H3 tail by an ASH2/WDR5/MLL-family methyltransferase complex. Chromatin immunoprecipitation showed that H3R2me2a was distributed within the body and at the 3' end of human genes, regardless of their transcriptional state, whereas it was selectively and locally depleted from active promoters, coincident with the presence of H3K4me3. Hence, the mutual antagonism between H3R2 and H3K4 methylation, together with the association of MLL-family complexes with the basal transcription machinery, may contribute to the localized patterns of H3K4 tri-methylation characteristic of transcriptionally poised or active promoters in mammalian genomes.
真核生物基因组被组织成活性（常染色质）和非活性（异染色质）染色质结构域。组蛋白的翻译后修饰（或“标记”）在定义这些功能状态中起关键作用，特别是在启动子区域。这些标记以及催化它们的酶之间的相互调节相互作用，以一种仍有待充分阐明的方式，促成了这种表观遗传景观的形成。我们之前观察到，组蛋白H3精氨酸2的不对称二甲基化（H3R2me2a）与人启动子上H3赖氨酸4的二甲基化和三甲基化（H3K4me2、H3K4me3）呈负相关。在此我们表明，精氨酸甲基转移酶PRMT6在体外催化H3R2的二甲基化，并在体内控制H3R2me2a的整体水平。H3尾部存在H3K4me3可阻止PRMT6对H3R2的甲基化。相反，H3R2me2a标记可阻止H3K4的甲基化以及ASH2/WDR5/MLL家族甲基转移酶复合物与H3尾部的结合。染色质免疫沉淀显示，H3R2me2a分布在人类基因的体内及3'端，无论其转录状态如何，而在活性启动子中它被选择性地局部耗尽，这与H3K4me3的存在一致。因此，H3R2和H3K4甲基化之间的相互拮抗作用，以及MLL家族复合物与基础转录机制的关联，可能有助于形成哺乳动物基因组中处于转录就绪或活跃状态的启动子所特有的H3K4三甲基化的局部模式。
