繼4個月前生化與細(xì)胞所陳德桂研究組與景乃禾研究組合作發(fā)表一個新的組蛋白去甲基化酶KIAA1718(KDM7A)的發(fā)現(xiàn)及其在胚胎干細(xì)胞神經(jīng)分化過程中的功能,，及兩周前陳德桂研究組基因敲除與轉(zhuǎn)基因小鼠平臺合作發(fā)表另一個新的組蛋白去甲基化酶PHF8 (KDM7B)的發(fā)現(xiàn)及其調(diào)控rRNA轉(zhuǎn)錄的研究后,，陳德桂研究組和復(fù)旦大學(xué)生物醫(yī)學(xué)研究院徐彥輝研究組合作進(jìn)一步用線蟲蛋白質(zhì)研究KDM7的作用機(jī)制，并用6種共結(jié)晶結(jié)構(gòu)解釋其作用機(jī)制,，該兩項研究在Cell Research上剛剛發(fā)表,。
與哺乳動物一樣，線蟲ceKDM7A也含有一個JmjC結(jié)構(gòu)域和PHD結(jié)構(gòu)域,，體外酶活實驗發(fā)現(xiàn)在不需要PHD結(jié)構(gòu)域情況下JmjC結(jié)構(gòu)域具有去除H3K9和H3K27二甲基的雙活性組蛋白去甲基化酶,，但在細(xì)胞內(nèi)卻需要PHD結(jié)構(gòu)域。PHD結(jié)構(gòu)域結(jié)合H3K4三甲基,，而且只有通過結(jié)合H3K4三甲基,，該酶在細(xì)胞內(nèi)才可以去除H3K9和H3K27二甲基。由于H3K9和H3K27二甲基與轉(zhuǎn)錄抑制相關(guān),，H3K4三甲基與轉(zhuǎn)錄激活相關(guān),，該研究提供了為什么與轉(zhuǎn)錄抑制相關(guān)的甲基化和與轉(zhuǎn)錄激活的甲基化不能在一起的解釋。
同時,，他們完成了含有不同組蛋白甲基化修飾肽段的6種共結(jié)晶,，從結(jié)構(gòu)上解釋了該酶催化的特異性和底物識別機(jī)理，并發(fā)現(xiàn)該酶結(jié)合的H3K4三甲基和催化的H3K9二甲基應(yīng)存在于不同的組蛋白上,。
該研究對組蛋白甲基化等表觀遺傳機(jī)理研究有積極意義,。該項工作得到了國家科技部,、國家自然科學(xué)基金委、中國科學(xué)院及上海市科委的經(jīng)費支持,。(生物谷www.Bioon.net)
生物谷推薦原文出處：
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.
