近日，中科院遺傳與發(fā)育生物學(xué)研究所韓敬東實(shí)驗(yàn)室的組蛋白修飾對(duì)衰老的調(diào)控機(jī)制研究，作為封面文章在線發(fā)表于國(guó)際著名學(xué)術(shù)期刊《細(xì)胞—代謝》（Cell Metabolism）。該雜志同期以preview的形式對(duì)這項(xiàng)研究給予了高度評(píng)價(jià)，認(rèn)為：“文章的實(shí)驗(yàn)證據(jù)表明，重新建立表觀遺傳狀態(tài)為延緩衰老甚至逆轉(zhuǎn)衰老提供了可能性，這是重要的發(fā)現(xiàn)。”
這項(xiàng)研究通過(guò)生物化學(xué)、分子生物學(xué)、遺傳學(xué)和系統(tǒng)生物學(xué)相結(jié)合的方法，發(fā)現(xiàn)組蛋白H3K27me2/3去甲基酶UTX-1/UTX對(duì)衰老發(fā)揮了重要的調(diào)控作用。在秀麗線蟲(chóng)中，該基因的雜合突變體及野生型的RNAi敲降后都能極大地延長(zhǎng)線蟲(chóng)壽命，使其抗逆性也大大加強(qiáng)。遺傳學(xué)分析發(fā)現(xiàn)其功能依賴于胰島素樣信號(hào)通路。這種通過(guò)重新建立組蛋白修飾模式的作用方式，揭示了細(xì)胞的重編程在抑制衰老過(guò)程中的重要作用，并提示其作用機(jī)制在哺乳動(dòng)物細(xì)胞中同樣存在。
該研究首次報(bào)道了通過(guò)體細(xì)胞發(fā)揮功能的組蛋白修飾基因?qū)λダ线@一重要生物學(xué)過(guò)程的調(diào)控作用，加深了對(duì)表觀遺傳功能的認(rèn)識(shí)，并為新型抗衰老藥物的研發(fā)提供了潛在的靶點(diǎn)。
因?yàn)檫@項(xiàng)工作是由中國(guó)本土實(shí)驗(yàn)室完成的，封面圖片也設(shè)計(jì)成中國(guó)風(fēng)格。
Histone Demethylase UTX-1 Regulates C. elegans Life Span by Targeting the Insulin/IGF-1 Signaling Pathway
Chunyu Jin, Jing Li, Christopher D. Green, Xiaoming Yu, Xia Tang, Dali Han, Bo Xian, Dan Wang, Xinxin Huang, Xiongwen Cao, Zheng Yan, Lei Hou, Jiancheng Liu, Nicholas Shukeir, Philipp Khaitovich, Charlie D. Chen, Hong Zhang, Thomas Jenuwein, Jing-Dong J. Han
Epigenetic modifications are thought to be important for gene expression changes during development and aging. However, besides the Sir2 histone deacetylase in somatic tissues and H3K4 trimethylation in germlines, there is scant evidence implicating epigenetic regulations in aging. The insulin/IGF-1 signaling (IIS) pathway is a major life span regulatory pathway. Here, we show that progressive increases in gene expression and loss of H3K27me3 on IIS components are due, at least in part, to increased activity of the H3K27 demethylase UTX-1 during aging. RNAi of the utx-1 gene extended the mean life span of C. elegans by ∼30%, dependent on DAF-16 activity and not additive in daf-2 mutants. The loss of utx-1 increased H3K27me3 on the Igf1r/daf-2 gene and decreased IIS activity, leading to a more “naive” epigenetic state. Like stem cell reprogramming, our results suggest that reestablishment of epigenetic marks lost during aging might help “reset” the developmental age of animal cells.
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