女科学家Nature解密不老传说

　　

生物通报道，费城wistar研究所基因表达与调控研究项目组、生化项目组、华盛顿大学病理学系等处的研究者在最新的Nature上发表细胞寿命研究的文章，Histone H4 lysine 16 acetylation regulates cellular lifespan。

 

文章通讯作者是来自Wistar研究所和宾夕法尼亚大学医学院的女科学家Shelley L. Berger。

 

细胞在发育的过程中具有一个典型的特征：遗传物质不发生变化，却一直发生表观遗传学的改变，甲基化和组蛋白修饰作用一直在改变细胞的发育。

 

Sirtuins是一类保守的NAD+依赖的脱乙酰基酶，具有通过各种途径延长有机体寿命的能力。然而，关于sirtunis调节寿命的分子机制却一直了解不多。

 

本研究中，Shelley L. Berger教授等人以酵母Sir2为研究对象，解析它对细胞寿命的调节机制。

 

Sir2蛋白可去除细胞的H4赖氨酸 -16乙酰化作用还可能诱导其他沉默蛋白的生成。在老化的酵母细胞中，Sir2蛋白逐步减少，并且伴随H4赖氨酸 -16乙酰化作用加剧，部分区域的组蛋白消失，这导致某些基因座的沉默机制停止。

 

这些结果表明Sirtuins从演化角度来讲其一个保守的功能，即通过使端粒染色质保持不变，来调控复制性衰老。

（生物通 小茜）

生物通推荐原文检索

Nature 459, 802-807 (11 June 2009) | doi:10.1038/nature08085; Received 3 February 2009; Accepted 21 April 2009

 

Histone H4 lysine 16 acetylation regulates cellular lifespan

Weiwei Dang1, Kristan K. Steffen2, Rocco Perry1, Jean A. Dorsey1, F. Brad Johnson4, Ali Shilatifard5, Matt Kaeberlein3, Brian K. Kennedy2 & Shelley L. Berger1,6

 

Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA

Department of Biochemistry,

Department of Pathology, University of Washington Seattle, Washington 98195, USA

Department of Pathology and Laboratory Medicine, Cell and Molecular Biology Group, Biomedical Graduate Studies and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia 19104, Pennsylvania, USA

Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA

Department of Cell & Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

【Abstract】

Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD+-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin.