Multiple knockout mouse models reveal lincRNAs are required for life and brain development.
Multiple knockout mouse models reveal lincRNAs are required for life and brain development.
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DOI：
10.7554/elife.01749
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发表时间：
2013-12-31
期刊：
影响因子：
7.7
通讯作者：
Rinn JL
中科院分区：
文献类型：
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作者：
Sauvageau M;Goff LA;Lodato S;Bonev B;Groff AF;Gerhardinger C;Sanchez-Gomez DB;Hacisuleyman E;Li E;Spence M;Liapis SC;Mallard W;Morse M;Swerdel MR;D'Ecclessis MF;Moore JC;Lai V;Gong G;Yancopoulos GD;Frendewey D;Kellis M;Hart RP;Valenzuela DM;Arlotta P;Rinn JL
许多研究正在揭示长非编码 RNA (lncRNA) 的功能作用，但很少有研究通过动物模型中的基因消融来测试体内相关性。为了研究 lncRNA 在各种生理条件下的功能相关性，我们开发了 18 个 lncRNA 敲除菌株的集合，其中基因座保持转录活性。初步表征揭示了三种突变株（Fendrr、Peril 和 Mdgt）的围产期和产后致死表型，后两种在幸存者中表现出不完全外显率和生长缺陷。我们还报告了另外两种突变菌株（linc-Brn1b 和 linc-Pint）的生长缺陷。进一步的分析显示，Fendrr−/− 新生儿的肺、胃肠道和心脏存在缺陷，而 linc–Brn1b−/− 突变体在新皮质中上层 II-IV 神经元的生成方面表现出明显的异常。这项研究表明lncRNA在体内发挥着关键作用，并为未来对lncRNA分子的作用进行更大规模的功能研究提供了框架和动力。 DOI：http://dx.doi.org/10.7554/eLife.01749.001 哺乳动物基因组由包含蛋白质模板的 DNA 序列和不编码蛋白质的其他 DNA 序列组成。编码 DNA 序列被转录形成信使 RNA 分子，然后翻译成蛋白质。研究人员多年来已经知道，一些非编码 DNA 序列也可以转录产生其他类型的 RNA 分子，例如转移 RNA 和核糖体 RNA。然而，这些其他 RNA 分子发挥的作用的真正广度和多样性直到最近才开始得到充分认识。哺乳动物基因组包含数千个可转录的非编码 DNA 序列。最近的体外研究表明，由此产生的长非编码 RNA 分子可以充当转录、翻译和细胞周期的调节因子。体外研究还表明，这些长非编码 RNA 分子可能在哺乳动物发育和疾病中发挥作用。然而，很少有体内研究来支持或证实这些假设。现在 Sauvageau 等人。开发了几种基因敲除小鼠品系，以研究称为长基因间非编码 RNA (lincRNA) 的非编码 RNA 分子子集。这些实验表明，lincRNA 对小鼠的整体生存能力以及许多发育过程（包括肺部和大脑皮层的发育）有很大的影响。鉴于绝大多数人类基因组都是转录的，Sauvageau 等人开发的小鼠模型。代表了在遗传水平上确定体内基因组非编码部分的生理相关性的重要一步。 DOI：http://dx.doi.org/10.7554/eLife.01749.002
Many studies are uncovering functional roles for long noncoding RNAs (lncRNAs), yet few have been tested for in vivo relevance through genetic ablation in animal models. To investigate the functional relevance of lncRNAs in various physiological conditions, we have developed a collection of 18 lncRNA knockout strains in which the locus is maintained transcriptionally active. Initial characterization revealed peri- and postnatal lethal phenotypes in three mutant strains (Fendrr, Peril, and Mdgt), the latter two exhibiting incomplete penetrance and growth defects in survivors. We also report growth defects for two additional mutant strains (linc–Brn1b and linc–Pint). Further analysis revealed defects in lung, gastrointestinal tract, and heart in Fendrr−/− neonates, whereas linc–Brn1b−/− mutants displayed distinct abnormalities in the generation of upper layer II–IV neurons in the neocortex. This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules. DOI: http://dx.doi.org/10.7554/eLife.01749.001 The mammalian genome is comprised of DNA sequences that contain the templates for proteins, and other DNA sequences that do not code for proteins. The coding DNA sequences are transcribed to make messenger RNA molecules, which are then translated to make proteins. Researchers have known for many years that some of the noncoding DNA sequences are also transcribed to make other types of RNA molecules, such as transfer and ribosomal RNA. However, the true breadth and diversity of the roles played by these other RNA molecules have only recently begun to be fully appreciated. Mammalian genomes contain thousands of noncoding DNA sequences that are transcribed. Recent in vitro studies suggest that the resulting long noncoding RNA molecules can act as regulators of transcription, translation, and cell cycle. In vitro studies also suggest that these long noncoding RNA molecules may play a role in mammalian development and disease. Yet few in vivo studies have been performed to support or confirm such hypotheses. Now Sauvageau et al. have developed several lines of knockout mice to investigate a subset of noncoding RNA molecules known as long intergenic noncoding RNAs (lincRNAs). These experiments reveal that lincRNAs have a strong influence on the overall viability of mice, and also on a number of developmental processes, including the development of lungs and the cerebral cortex. Given that the vast majority of the human genome is transcribed, the mouse models developed by Sauvageau et al. represent an important step in determining the physiological relevance, on a genetic level, of the noncoding portion of the genome in vivo. DOI: http://dx.doi.org/10.7554/eLife.01749.002