Cui Liwang, Fan Qi, Cui Long, Miao Jun
Department of Entomology, The Pennsylvania State University, 501 ASI Building, University Park, PA 16802, USA.
Int J Parasitol. 2008 Aug;38(10):1083-97. doi: 10.1016/j.ijpara.2008.01.002. Epub 2008 Jan 26.
Dynamic histone lysine methylation, regulated by methyltransferases and demethylases, plays fundamental roles in chromatin structure and gene expression in a wide range of eukaryotic organisms. A large number of SET-domain-containing proteins make up the histone lysine methyltransferase (HKMT) family, which catalyses the methylation of different lysine residues with relatively high substrate specificities. Another large family of Jumonji C (JmjC)-domain-containing histone lysine demethylases (JHDMs) reverses histone lysine methylation with both lysine site and methyl-state specificities. Through bioinformatic analysis, at least nine SET-domain-containing genes were found in the malaria parasite Plasmodium falciparum and its sibling species. Phylogenetic analysis separated these putative HKMTs into five subfamilies with different putative substrate specificities. Consistent with the phylogenetic subdivision, methyl marks were found on K4, K9 and K36 of histone H3 and K20 of histone H4 by site-specific methyl-lysine antibodies. In addition, most SET-domain genes and histone methyl-lysine marks displayed dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites. Furthermore, the malaria parasite and other apicomplexan genomes also encode JmjC-domain-containing proteins that may serve as histone lysine demethylases. Whereas prokaryotic expression of putative active domains of four P. falciparum SET proteins did not yield detectable HKMT activity towards recombinant P. falciparum histones, two protein domains expressed in vitro in a eukaryotic system showed HKMT activities towards H3 and H4, respectively. With the discovery of these Plasmodium SET- and JmjC-domain genes in the malaria parasite genomes, future efforts will be directed towards elucidation of their substrate specificities and functions in various cellular processes of the parasites.
由甲基转移酶和去甲基酶调控的动态组蛋白赖氨酸甲基化，在广泛的真核生物的染色质结构和基因表达中发挥着重要作用。大量含SET结构域的蛋白质构成了组蛋白赖氨酸甲基转移酶（HKMT）家族，该家族以相对较高的底物特异性催化不同赖氨酸残基的甲基化。另一大组含Jumonji C（JmjC）结构域的组蛋白赖氨酸去甲基酶（JHDM）家族则以赖氨酸位点和甲基化状态特异性逆转组蛋白赖氨酸甲基化。通过生物信息学分析，在疟原虫恶性疟原虫及其近缘物种中发现了至少九个含SET结构域的基因。系统发育分析将这些假定的HKMT分为五个亚家族，具有不同的假定底物特异性。与系统发育细分一致，通过位点特异性甲基赖氨酸抗体在组蛋白H3的K4、K9和K36以及组蛋白H4的K20上发现了甲基标记。此外，大多数SET结构域基因和组蛋白甲基赖氨酸标记在寄生虫无性红细胞周期中表现出动态变化，这表明它们构成了疟原虫基因调控的重要表观遗传机制。此外，疟原虫和其他顶复门基因组也编码可能作为组蛋白赖氨酸去甲基酶的含JmjC结构域的蛋白质。虽然四种恶性疟原虫SET蛋白的假定活性结构域的原核表达未产生针对重组恶性疟原虫组蛋白的可检测HKMT活性，但在真核系统中体外表达的两个蛋白结构域分别对H3和H4显示出HKMT活性。随着在疟原虫基因组中发现这些疟原虫SET和JmjC结构域基因，未来的工作将致力于阐明它们在寄生虫各种细胞过程中的底物特异性和功能。
