Silencing of Parkinson's disease-associated genes with artificial mirtron mimics of miR-1224.
Silencing of Parkinson's disease-associated genes with artificial mirtron mimics of miR-1224.
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DOI：
10.1093/nar/gks712
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发表时间：
2012-10
影响因子：
14.9
通讯作者：
Wood MJ
中科院分区：
文献类型：
--
作者：
Sibley CR;Seow Y;Curtis H;Weinberg MS;Wood MJ
Mirtrons是最近被描述的一类microRNA(MiRNA)，它依赖剪接而不是微处理器复合体的处理来产生RNA干扰(RNAi)途径的前miRNA前体。他们的发现和随后的验证提供了关于一类独特的miRNA的重要信息，以及可以利用来沉默感兴趣基因的固有优势。这些包括微处理器独立的生物发生，PolII依赖的转录，准确的物种生成，以及在单个宿主转录本中作为内含子递送多个人工微子。在这里，我们确定了正确处理MMU-miR-1224mirtron所需的序列基序，并将这些序列基序整合到针对帕金森氏症相关LRRK2和α-Synuclein基因的人工镜像中。通过将这些与加工和剪接相关的规则结合起来，可以设计和制造人工镜像，以在mRNA或蛋白质水平上沉默互补靶标。我们进一步用靶向人工Mirtron的LRRK2证明了神经元特异性沉默可以在人类突触素启动子的控制下进行。最后，在单个宿主转录本中共同传递多个镜像，即EGFP报告，以允许以组合方法同时靶向两个或更多个靶点。因此，人工镜像的独特特性使其成为未来RNAi应用的一种有吸引力的方法。
Mirtrons are a recently described category of microRNA (miRNA) relying on splicing rather than processing by the microprocessor complex to generate pre-miRNA precursors of the RNA interference (RNAi) pathway. Their discovery and subsequent verification provides important information about a distinct class of miRNA and inherent advantages that could be exploited to silence genes of interest. These include micro-processor-independent biogenesis, pol-II-dependent transcription, accurate species generation and the delivery of multiple artificial mirtrons as introns within a single host transcript. Here we determined the sequence motifs required for correct processing of the mmu-miR-1224 mirtron and incorporated these into artificial mirtrons targeting Parkinson’s disease-associated LRRK2 and α-synuclein genes. By incorporating these rules associated with processing and splicing, artificial mirtrons could be designed and made to silence complementary targets either at the mRNA or protein level. We further demonstrate with a LRRK2 targeting artificial mirtron that neuronal-specific silencing can be directed under the control of the human synapsin promoter. Finally, multiple mirtrons were co-delivered within a single host transcript, an eGFP reporter, to allow simultaneous targeting of two or more targets in a combinatorial approach. Thus, the unique characteristics of artificial mirtrons make this an attractive approach for future RNAi applications.
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影响因子：
16.2
作者：
Lin, Xian;Parisiadou, Loukia;Gu, Xing-Long;Wang, Lizhen;Shim, Hoon;Sun, Lixin;Xie, Chengsong;Long, Cai-Xia;Yang, Wan-Jou;Ding, Jinhui;Chen, Zsu Zsu;Gallant, Paul E.;Tao-Cheng, Jung-Hwa;Rudow, Gay;Troncoso, Juan C.;Liu, Zhihua;Li, Zheng;Cai, Huaibin
通讯作者：
Cai, Huaibin
影响因子：
14.9
作者：
Gao K;Masuda A;Matsuura T;Ohno K
通讯作者：
Ohno K
影响因子：
64.5
作者：
Han, Jinju;Lee, Yoontae;Kim, V. Narry
通讯作者：
Kim, V. Narry
影响因子：
64.8
作者：
Grimm, Dirk;Streetz, Konrad L.;Kay, Mark A.
通讯作者：
Kay, Mark A.
DOI：
10.1038/nrd2310
发表时间：
2007-06
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
de Fougerolles A;Vornlocher HP;Maraganore J;Lieberman J
通讯作者：
Lieberman J