前沿研究：小RNA与基因组稳定性
时间： 2011-11-28 点击次数：次 作者：admin
Small RNAs & Genomics Stability
小RNA与基因组稳定性
生物体的生殖系细胞担负着遗传信息的世代传递，其基因组的完整性对于个体和物种维持都至关重要。而基因组中大量存在的转座子等DNA移动元件则有可能引发基因组突变。科学家们在研究中证实生物体通常会利用一些小RNA分子引导蛋白质去沉默基因组中的转座子。这些信号通路普遍存在于原核细胞和真核细胞中，并在物种间以保守的机制发挥作用，其中包括识别外源遗传元件，激活沉默反应，维持活性转座子事件“记忆”等。而与这些Piwi蛋白相关的小RNA（称作pi RNAs）在这些过程中发挥了关键性的作用。
这种特殊的RNA最早是2006年来自冷泉港实验室的格雷格•汉农研究小组和纽约洛克菲勒大学的托马斯研究小组在对老鼠睾丸中的所有RNA编码时发现的。科学家们当时在对无脊椎动物和小鼠中对精子细胞发育过程中起重要作用的Piwi蛋白进行分析时，发现这种蛋白质上附着了一类新的RNA，因此将这类新RNA命名为“PIWI互动RNA”（简称pi RNAs）。而几乎在同时，来自波士顿的罗伯特•金斯顿和他的同事们也在大鼠的睾丸提取物中发现了piRNA。比起已发现的其他小分子RNA，30个核苷酸左右的piRNA要稍长。格雷格•汉农等发现piRNA大小约为29—30个核苷酸，而托马斯等人的结果稍有出入，在26—31个核苷酸左右。
通过对RNA染色，研究者们在其他哺乳动物的睾丸中也找到了潜在的这类piRNA，包括人类、大鼠以及公牛。这些物种中的piRNA和小鼠的具有同样的特征，如起始端尿嘧啶强偏好性以及长度在30个核苷酸左右等。
鉴于piRNA主要分布在包括人类等数种动物体睾丸的精原细胞内，科学家们推测这类小分子RNA功能可能与动物体精子的发育和维持相关。
2007年，Brennecke等提出piRNA信号可能是作为一个分子适应性免疫系统，感知并对抗沉默外来入侵遗传元件功能。
近年来随着针对piRNA信号研究的深入展开，科学家们普遍认为piRNA途径可能是动物生殖细胞进化获得的一个独特的对抗外来入侵遗传元件、维持自身基因组稳定和完整的作用通路，推测piRNA可能在表观遗传水平和转录后水平沉默转座子、逆转座子等DNA移动元件。
目前针对piRNA的研究大体的研究方向主要分为pi RNAs对转座子的调控，pi RNA的生物起源和功能以及在维持基因组稳定性上保守的分子机制等。
最近，Cell杂志也针对科学家们在这几个研究方向上获得的突破性研究成果推荐了从2009年到2011年发表在Cell及子刊上的15篇pi RNA研究论文，供这一研究领域的科研工作者参考。
Cells must control transposons and foreign genetic elements to maintain genomic stability. This is especially important in gametes, where unchecked transposon activity could affect the next generation. We now know that organisms have pathways in which small RNAs guide proteins to actively silence transposons in the genome. These pathways exist in prokaryotes and eukaryotes, with general mechanisms conserved between the two groups. These include mechanisms for recognizing foreign genetic elements, activating the silencing responses, and maintaining a "memory" of the active transposon event. Small RNAs associated with piwi proteins — known as piRNAs — are critical to these processes.
In 2007,Brennecke et al.proposed that the piRNA pathway could act as a molecular adaptive immune system, capable of sensing and reacting to adaptive transposons by silencing them. We begin this Collection looking back at these findings and then taking a broader view to appreciate how much we have learned about the roles of small RNAs in the maintenance of genomic stability.
Discrete Small RNA-Generating Loci as Master Regulators of Transposon Activity in Drosophila. Julius Brennecke, Alexei A. Aravin, Alexander Stark, Monica Dus, Manolis Kellis, Ravi Sachidanandam, Gregory J. Hannon
SnapShot: Mouse piRNAs, PIWI Proteins, and the Ping-Pong Cycle Jogender S. Tushir, Phillip D. Zamore, Zhao Zhang
1、piRNAs in Transposon Control
Small RNAs as Guardians of the Genome, Colin D. Malone, Gregory J. Hannon, Cell, February 20, 2009
3' End Formation of PIWI-Interacting RNAs In Vitro, Shinpei Kawaoka, Natsuko Izumi, Susumu Katsuma, Yukihide Tomari, Cell, September 16, 2011
The Drosophila HP1 Homolog Rhino Is Required for Transposon Silencing and piRNA Production by Dual-Strand Cluster, Carla Klattenhoff, Hualin Xi, Chengjian Li, Soohyun Lee, Jia Xu, Jaspreet S. Khurana, Fan Zhang, Nadine Schultz, Birgit S. Koppetsch, Anetta Nowosielska et al. Cell, September 18, 2009
2、Cell Biology of piRNA Biogenesis and Function
MITOPLD Is a Mitochondrial Protein Essential for Nuage Formation and piRNA Biogenesis in the Mouse Germline, Toshiaki Watanabe, Shinichiro Chuma, Yasuhiro Yamamoto, Satomi Kuramochi-Miyagawa, Yasushi Totoki, Atsushi Toyoda, Yuko Hoki, Asao Fujiyama et al. Cell, March 15, 2011
piRNA-Associated Germline Nuage Formation and Spermatogenesis Require MitoPLD Profusogenic Mitochondrial-Surface Lipid Signaling, Huiyan Huang, Qun Gao, Xiaoxue Peng, Seok-Yong Choi, Krishna Sarma, Hongmei Ren, Andrew J. Morris, Michael A. Frohman, Developmental Cell, March 15, 2011
The TDRD9-MIWI2 Complex Is Essential for piRNA-Mediated Retrotransposon Silencing in the Mouse Male Germline, Masanobu Shoji, Takashi Tanaka, Mihoko Hosokawa, Michael Reuter, Alexander Stark, Yuzuru Kato, Gen Kondoh, Katsuya Okawa, Takeshi Chujo et al. Developmental Cell, December 15, 2009
Specialized piRNA Pathways Act in Germline and Somatic Tissues of the Drosophila Ovary, Colin D. Malone, Julius Brennecke, Monica Dus, Alexander Stark, W. Richard McCombie, Ravi Sachidanandam, Gregory J. Hannon, Cell, May 1, 2009
Collapse of Germline piRNAs in the Absence of Argonaute3 Reveals Somatic piRNAs in Flies, Chengjian Li, Vasily V. Vagin, Soohyun Lee, Jia Xu, Shengmei Ma, Hualin Xi, Hervé Seitz, Michael D. Horwich, Monika Syrzycka, Barry M. Honda et al. Cell, May 1, 2009
3、A Conserved Approach to Genomic Stability
The CRISPR System: Small RNA-Guided Defense in Bacteria and Archaea, Fedor V. Karginov, Gregory J. Hannon, Molecular Cell, January 15, 2010
Article: RNA-Guided RNA Cleavage by a CRISPR RNA-Cas Protein Complex, Caryn R. Hale, Peng Zhao, Sara Olson, Michael O. Duff, Brenton R. Graveley, Lance Wells, Rebecca M. Terns, Michael P. Terns, Cell, November 25, 2009
Distinct Argonaute-Mediated 22G-RNA Pathways Direct Genome Survillance in the C. elegans Germline, Weifeng Gu, Masaki Shirayama, Darryl Conte, Jessica Vasale, Pedro J. Batista, Julie M. Claycomb, James J. Moresco, Elaine M. Youngman, Jennifer Keys et al. Molecular Cell, October 2, 2009
Article: CDE-1 Affects Chromosome Segregation through Uridylation of CSR-1-Bound siRNAs, Josien C. van Wolfswinkel, Julie M. Claycomb, Pedro J. Batista, Craig C. Mello, Eugene Berezikov, René F. Ketting, Cell, October 2, 2009
Epigenetic Reprogramming and Small RNA Silencing of Transposable Elements in Pollen, R. Keith Slotkin, Matthew Vaughn, Filipe Borges, Milos Tanurdzic, Jörg D. Becker, Josë A. Feijó, Robert A. Martienssen, Cell, February 6, 2009