Cell Metab.:韩敬东等发现组蛋白修饰对衰老调控机制

上一篇 / 下一篇  2011-08-26 21:50:24

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近日,中科院遗传与发育生物学研究所韩敬东实验室的组蛋白修饰对衰老的调控机制研究,作为封面文章在线发表于国际著名学术期刊《细胞—代谢》(Cell Metabolism)。该杂志同期以preview的形式对这项研究给予了高度评价,认为:“文章的实验证据表明,重新建立表观遗传状态为延缓衰老甚至逆转衰老提供了可能性,这是重要的发现。”

这项研究通过生物化学、分子生物学、遗传学和系统生物学相结合的方法,发现组蛋白H3K27me2/3去甲基酶UTX-1/UTX对衰老发挥了重要的调控作用。在秀丽线虫中,该基因的杂合突变体及野生型的RNAi敲降后都能极大地延长线虫寿命,使其抗逆性也大大加强。遗传学分析发现其功能依赖于胰岛素样信号通路。这种通过重新建立组蛋白修饰模式的作用方式,揭示了细胞的重编程在抑制衰老过程中的重要作用,并提示其作用机制在哺乳动物细胞中同样存在。

该研究首次报道了通过体细胞发挥功能的组蛋白修饰基因对衰老这一重要生物学过程的调控作用,加深了对表观遗传功能的认识,并为新型抗衰老药物的研发提供了潜在的靶点。

因为这项工作是由中国本土实验室完成的,封面图片也设计成中国风格。

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

Epigeneticmodifications 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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