继4个月前生化与细胞所陈德桂研究组与景乃禾研究组合作发表一个新的组蛋白去甲基化酶KIAA1718(KDM7A)的发现及其在胚胎干细胞神经分化过程中的功能,及两周前陈德桂研究组基因敲除与转基因小鼠平台合作发表另一个新的组蛋白去甲基化酶PHF8 (KDM7B)的发现及其调控rRNA转录的研究后,陈德桂研究组和复旦大学生物医学研究院徐彦辉研究组合作进一步用线虫蛋白质研究KDM7的作用机制,并用6种共结晶结构解释其作用机制,该两项研究在Cell Research上刚刚发表。
与哺乳动物一样,线虫ceKDM7A也含有一个JmjC结构域和PHD结构域,体外酶活实验发现在不需要PHD结构域情况下JmjC结构域具有去除H3K9和H3K27二甲基的双活性组蛋白去甲基化酶,但在细胞内却需要PHD结构域。PHD结构域结合H3K4三甲基,而且只有通过结合H3K4三甲基,该酶在细胞内才可以去除H3K9和H3K27二甲基。由于H3K9和H3K27二甲基与转录抑制相关,H3K4三甲基与转录激活相关,该研究提供了为什么与转录抑制相关的甲基化和与转录激活的甲基化不能在一起的解释。
同时,他们完成了含有不同组蛋白甲基化修饰肽段的6种共结晶,从结构上解释了该酶催化的特异性和底物识别机理,并发现该酶结合的H3K4三甲基和催化的H3K9二甲基应存在于不同的组蛋白上。
该研究对组蛋白甲基化等表观遗传机理研究有积极意义。该项工作得到了国家科技部、国家自然科学基金委、中国科学院及上海市科委的经费支持。
原文出处:
Cell Research doi: 10.1038/cr.2010.84
Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans
Hanqing Lin1, Yiqin Wang1, Yanru Wang1,2, Feng Tian1, Pu Pu1, Yi Yu1, Hailei Mao1,2, Ying Yang3,4, Ping Wang3,4, Lulu Hu3,4, Yan Lin3,4, Yi Liu3,4, Yanhui Xu3,4 and Charlie Degui Chen1
1State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
2Affiliated Hospital of Nantong University, Nantong 226001, China
3School of Life Sciences, Fudan University, 220 Han-Dan Road, Shanghai 200433, China
4Institutes of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China
H3K9me2 and H3K27me2 are important epigenetic marks associated with transcription repression, while H3K4me3 is associated with transcription activation. It has been shown that active and repressive histone methylations distribute in a mutually exclusive manner, but the underlying mechanism was poorly understood. Here we identified ceKDM7A, a PHD (plant homeodomain)- and JmjC domain-containing protein, as a histone demethylase specific for H3K9me2 and H3K27me2. We further demonstrated that the PHD domain of ceKDM7A bound H3K4me3 and H3K4me3 co-localized with ceKDM7A at the genome-wide level. Disruption of the PHD domain binding to H3K4me3 reduced the demethylase activity in vivo, and loss of ceKDM7A reduced the expression of its associated target genes. These results indicate that ceKDM7A is recruited to the promoter to demethylate H3K9me2 and H3K27me2 and activate gene expression through the binding of the PHD domain to H3K4me3. Thus, our study identifies a dual-specificity histone demethylase and provides novel insights into the regulation of histone methylation.