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RNA激活

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RNA激活（RNA activation, RNAa) 是一种由小分子RNA介导的特异性基因表达上调机制，是李龙承等[1]于2006年首先在人细胞中发现并命名的。随后，其他研究小组也报道了相似的现象，证明了RNA激活是从人及大小鼠等哺乳类动物到植物及线虫中的保守现象[2][3][4][5][6][7][8][9][10]。RNA激活是由靶向基因启动子区域的双链小RNA（dsRNA）分子介导并需要Argonaute（AGO）蛋白的参与[1][11]。这类能够诱导RNA激活现象（即激活基因表达）的dsRNA被称为小激活RNA（small activating RNA，saRNA）[12]。saRNA可通过人工设计及化学合成而获得，也可为天然存在的内源性RNA如miRNA；前者介导的RNA激活被称为外源性RNA激活，后者为内源性RNA激活。

与RNA干扰（RNAi）的异同

介导外源性RNA激活的saRNA与介导RNAi的siRNA结构相似， 是含21个核苷酸的双链RNA（dsRNA），其兩条链在各自的3’端含2个核苷酸的突出。和RNAi一样，RNAa也需要AGO蛋白特别是AGO2的参与，其作用可能是处理和活化saRNA分子，并介导saRNA与其启动子上的靶位点结合。与RNAi（主要发生在胞浆）不同的是，RNA激活机制发生在细胞核，介导RNA激活的saRNA靶向启动子而不是mRNA序列，此外，RNA激活具有特殊的时效性，表现为其效果（基因表达上调）的出现呈现48小时左右的滞后，及效果的长久性（10-14天）[1][13][14]。其机制被认为是因为RNA激活导致了表观遗传的改变[15]。

内源性RNA激活

2008年Place等[16]报道了天然存在的miRNA也能够靶向启动子序列而诱导RNA激活。他们发现人CDH1及CSDC2基因启动子存在miR-373的靶位点，在人肿瘤细胞中引入miR-373的模拟物（mimics）能激活其靶基因的表达。后来，Huang等进一步证实了内源性miRNA介导的RNAa，并且发现该机制在正常及肿瘤细胞的增殖中起重要作用[17]。Xiao等还报道了靶向增强子区域的miRNA也能够诱导RNA激活[18]。Chaluvally-Raghavan等发现miR-551b-3p通过靶向激活STAT3而促进卵巢癌细胞增殖、生存和肿瘤生长[19]。目前对于有多少基因受到内源性RNA激活机制的调控还不清楚，但有研究发现miRNA[20]及AGO蛋白[21]在人基因组的启动子区存在广泛的结合位点，提示miRNA可能在转录或者表观遗传水平调控大量的基因。

RNA激活的应用

RNA激活是一种简单易行的上调基因表达的方法，在生物医学领域具有广泛的潜在用途，包括作为工具用于研究基因的功能[22]和对细胞进行重新编程[23][24][25][26]，以及作为治疗疾病的手段，包括肿瘤、心血管疾病、勃起功能障碍等[27][28][29][30][31][32]。目前，治疗肝癌的saRNA药已经进入临床试验[28]。

參考來源

  1. ^ 1.0 1.1 1.2 Li LC, Okino ST, Zhao H; et al. Small dsRNAs induce transcriptional activation in human cells. Proc. Natl. Acad. Sci. U.S.A. November 2006, 103 (46): 17337–42. PMC 1859931 可免费查阅. PMID 17085592. doi:10.1073/pnas.0607015103. 
  2. ^ Janowski BA, Younger ST, Hardy DB, Ram R, Huffman KE, Corey DR. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat. Chem. Biol. March 2007, 3 (3): 166–73. PMID 17259978. doi:10.1038/nchembio860. 
  3. ^ Li LC. Small RNA-Mediated Gene Activation. RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. 2008 [2011-12-13]. ISBN 978-1-904455-25-7. （原始内容存档于2012-01-02）. 
  4. ^ Check E. RNA interference: hitting the on switch. Nature. 2007, 448 (7156): 855–8. PMID 17713502. doi:10.1038/448855a. 
  5. ^ Huang V; et al. RNAa is conserved in mammalian cells. PLoS One. 2010, 5 (1): e8848 [2011-12-13]. PMC 2809750 可免费查阅. PMID 20107511. doi:10.1371/journal.pone.0008848. （原始内容存档于2011-08-14）. 
  6. ^ Turunen MP, Lehtola T, Heinonen SE, Assefa GS, Korpisalo P; et al. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy. Circ Res. 2009, 105 (6): 604–609 [2011-12-13]. （原始内容存档于2014-10-21）. 
  7. ^ Meng, Xing; Jiang, Qian; Chang, Nannan; Wang, Xiaoxia; Liu, Chujun; Xiong, Jingwei; Cao, Huiqing; Liang, Zicai. Small activating RNA binds to the genomic target site in a seed-region-dependent manner. Nucleic Acids Research. 2016-03-18, 44 (5): 2274–2282 [2018-08-20]. ISSN 1362-4962. PMC 4797303 可免费查阅. PMID 26873922. doi:10.1093/nar/gkw076. （原始内容存档于2018-08-20）. 
  8. ^ Shibuya, Kenichi; Fukushima, Setsuko; Takatsuji, Hiroshi. RNA-directed DNA methylation induces transcriptional activation in plants. Proceedings of the National Academy of Sciences of the United States of America. 2009-02-03, 106 (5): 1660–1665 [2018-08-20]. ISSN 1091-6490. PMC 2629447 可免费查阅. PMID 19164525. doi:10.1073/pnas.0809294106. （原始内容存档于2018-08-21）. 
  9. ^ Seth, Meetu; Shirayama, Masaki; Gu, Weifeng; Ishidate, Takao; Conte, Darryl; Mello, Craig C. The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression. Developmental Cell. 2013-12-23, 27 (6): 656–663 [2018-08-20]. ISSN 1878-1551. PMC 3954781 可免费查阅. PMID 24360782. doi:10.1016/j.devcel.2013.11.014. （原始内容存档于2018-08-21）. 
  10. ^ Turner, Michael J.; Jiao, Alan L.; Slack, Frank J. Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans. Cell Cycle (Georgetown, Tex.). 2014, 13 (5): 772–781 [2018-08-20]. ISSN 1551-4005. PMC 3979913 可免费查阅. PMID 24398561. doi:10.4161/cc.27679. （原始内容存档于2018-08-20）. 
  11. ^ Portnoy, Victoria; Lin, Szu Hua Sharon; Li, Kathy H.; Burlingame, Alma; Hu, Zheng-Hui; Li, Hao; Li, Long-Cheng. saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription. Cell Research. 2016-3, 26 (3): 320–335 [2018-08-20]. ISSN 1748-7838. PMC 4783471 可免费查阅. PMID 26902284. doi:10.1038/cr.2016.22. （原始内容存档于2018-08-21）. 
  12. ^ Small Activating RNA Molecules and Methods of Use, 2014-10-01 [2018-08-20], （原始内容存档于2019-02-17） 
  13. ^ Place, Robert F.; Noonan, Emily J.; Földes-Papp, Zeno; Li, Long-Cheng. Defining features and exploring chemical modifications to manipulate RNAa activity. Current Pharmaceutical Biotechnology. 2010-8, 11 (5): 518–526 [2018-08-20]. ISSN 1873-4316. PMC 3413318 可免费查阅. PMID 20662764. （原始内容存档于2018-08-21）. 
  14. ^ Reebye, Vikash; Sætrom, Pål; Mintz, Paul J.; Huang, Kai-Wen; Swiderski, Piotr; Peng, Ling; Liu, Cheng; Liu, Xiaoxuan; Lindkaer-Jensen, Steen. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology (Baltimore, Md.). 2014-1, 59 (1): 216–227 [2018-08-20]. ISSN 1527-3350. PMC 4655108 可免费查阅. PMID 23929703. doi:10.1002/hep.26669. （原始内容存档于2018-08-20）. 
  15. ^ Portnoy V, Huang V, Place RF, Li LC. Small RNA and transcriptional upregulation. Wiley Interdiscip Rev RNA. 2011, 2 (5): 748–60 [2011-12-13]. doi:10.1002/wrna.90. （原始内容存档于2015-05-26）. 
  16. ^ Place RF, Li LC, Pookot D, Noonan EJ; et al. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A. 2008, 105 (5): 1608–13 [2011-12-13]. （原始内容存档于2012-06-01）. 
  17. ^ Huang V, Place RF, Portnoy V, Wang J, Qi Z, Jia Z, Yu A, Shuman M, Yu J, Li LC. Upregulation of Cyclin B1 by miRNA and its implications in cancer. Nucleic Acids Res. 2011 Nov 3. [Epub ahead of print] [2011-12-13]. （原始内容存档于2014-06-07）. 
  18. ^ Zou, Qingping; Liang, Ying; Luo, Huaibing; Yu, Wenqiang. miRNA-Mediated RNAa by Targeting Enhancers. Advances in Experimental Medicine and Biology. 2017, 983: 113–125 [2018-08-20]. ISSN 0065-2598. PMID 28639195. doi:10.1007/978-981-10-4310-9_8. （原始内容存档于2018-08-20）. 
  19. ^ Chaluvally-Raghavan, Pradeep; Jeong, Kang Jin; Pradeep, Sunila; Silva, Andreia Machado; Yu, Shuangxing; Liu, Wenbin; Moss, Tyler; Rodriguez-Aguayo, Cristian; Zhang, Dong. Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer. Cell Reports. 2016-05-17, 15 (7): 1493–1504 [2018-08-20]. ISSN 2211-1247. PMC 4914391 可免费查阅. PMID 27160903. doi:10.1016/j.celrep.2016.04.034. （原始内容存档于2018-08-20）. 
  20. ^ Paugh, Steven W.; Coss, David R.; Bao, Ju; Laudermilk, Lucas T.; Grace, Christy R.; Ferreira, Antonio M.; Waddell, M. Brett; Ridout, Granger; Naeve, Deanna. MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression. PLoS computational biology. 2016-2, 12 (2): e1004744 [2018-08-20]. ISSN 1553-7358. PMC 4742280 可免费查阅. PMID 26844769. doi:10.1371/journal.pcbi.1004744. （原始内容存档于2018-08-20）. 
  21. ^ Huang, Vera; Zheng, Jiashun; Qi, Zhongxia; Wang, Ji; Place, Robert F.; Yu, Jingwei; Li, Hao; Li, Long-Cheng. Ago1 Interacts with RNA polymerase II and binds to the promoters of actively transcribed genes in human cancer cells. PLoS genetics. 2013, 9 (9): e1003821 [2018-08-20]. ISSN 1553-7404. PMC 3784563 可免费查阅. PMID 24086155. doi:10.1371/journal.pgen.1003821. （原始内容存档于2018-08-20）. 
  22. ^ Wang, Ji; Place, Robert F.; Huang, Vera; Wang, Xiaoling; Noonan, Emily J.; Magyar, Clara E.; Huang, Jiaoti; Li, Long-Cheng. Prognostic value and function of KLF4 in prostate cancer: RNAa and vector-mediated overexpression identify KLF4 as an inhibitor of tumor cell growth and migration. Cancer Research. 2010-12-15, 70 (24): 10182–10191 [2018-08-20]. ISSN 1538-7445. PMC 3076047 可免费查阅. PMID 21159640. doi:10.1158/0008-5472.CAN-10-2414. （原始内容存档于2018-08-20）. 
  23. ^ Wang, Ji; Huang, Vera; Ye, Lin; Bárcena, Alicia; Lin, Guiting; Lue, Tom F.; Li, Long-Cheng. Identification of small activating RNAs that enhance endogenous OCT4 expression in human mesenchymal stem cells. Stem Cells and Development. 2015-02-01, 24 (3): 345–353 [2018-08-20]. ISSN 1557-8534. PMC 4303016 可免费查阅. PMID 25232932. doi:10.1089/scd.2014.0290. （原始内容存档于2018-08-20）. 
  24. ^ Wang, Xiaoling; Wang, Ji; Huang, Vera; Place, Robert F.; Li, Long-Cheng. Induction of NANOG expression by targeting promoter sequence with small activating RNA antagonizes retinoic acid-induced differentiation. The Biochemical Journal. 2012-05-01, 443 (3): 821–828 [2018-08-20]. ISSN 1470-8728. PMC 3327998 可免费查阅. PMID 22339500. doi:10.1042/BJ20111491. （原始内容存档于2018-08-20）. 
  25. ^ Esseltine, Jessica L.; Shao, Qing; Huang, Tao; Kelly, John J.; Sampson, Jacinda; Laird, Dale W. Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients. The Biochemical Journal. 2015-11-15, 472 (1): 55–69 [2018-08-20]. ISSN 1470-8728. PMID 26349540. doi:10.1042/BJ20150652. （原始内容存档于2018-08-21）. 
  26. ^ Reebye, Vikash; Sætrom, Pål; Mintz, Paul J.; Rossi, John J.; Kasahara, Noriyuki; Nteliopoulos, Georgios; Nicholls, Joanna; Haoudi, Abdelali; Gordon, Myrtle. A Short-activating RNA Oligonucleotide Targeting the Islet β-cell Transcriptional Factor MafA in CD34(+) Cells. Molecular Therapy. Nucleic Acids. 2013-06-04, 2: e97 [2018-08-20]. ISSN 2162-2531. PMC 3696904 可免费查阅. PMID 23736775. doi:10.1038/mtna.2013.23. （原始内容存档于2018-08-20）. 
  27. ^ Chen, Ruibao; Wang, Tao; Rao, Ke; Yang, Jun; Zhang, Shilin; Wang, Shaogang; Liu, Jihong; Ye, Zhangqun. Up-regulation of VEGF by small activator RNA in human corpus cavernosum smooth muscle cells. The Journal of Sexual Medicine. 2011-10, 8 (10): 2773–2780 [2018-08-20]. ISSN 1743-6109. PMID 21819543. doi:10.1111/j.1743-6109.2011.02412.x. （原始内容存档于2018-08-20）. 
  28. ^ 28.0 28.1 First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov. [2018-08-20]. （原始内容存档于2018-08-20） （英语）. 
  29. ^ Kang, Moo Rim; Yang, Glen; Place, Robert F.; Charisse, Klaus; Epstein-Barash, Hila; Manoharan, Muthiah; Li, Long-Cheng. Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth. Cancer Research. 2012-10-01, 72 (19): 5069–5079 [2018-08-20]. ISSN 1538-7445. PMID 22869584. doi:10.1158/0008-5472.CAN-12-1871. （原始内容存档于2018-08-21）. 
  30. ^ Voutila, Jon; Reebye, Vikash; Roberts, Thomas C.; Protopapa, Pantelitsa; Andrikakou, Pinelopi; Blakey, David C.; Habib, Robert; Huber, Hans; Saetrom, Pal. Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer. Molecular Therapy: The Journal of the American Society of Gene Therapy. 2017-12-06, 25 (12): 2705–2714 [2018-08-20]. ISSN 1525-0024. PMC 5768526 可免费查阅. PMID 28882451. doi:10.1016/j.ymthe.2017.07.018. （原始内容存档于2018-08-20）. 
  31. ^ Turunen, Mikko P.; Lehtola, Tiia; Heinonen, Suvi E.; Assefa, Genet S.; Korpisalo, Petra; Girnary, Roseanne; Glass, Christopher K.; Väisänen, Sami; Ylä-Herttuala, Seppo. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy. Circulation Research. 2009-09-11, 105 (6): 604–609 [2018-08-20]. ISSN 1524-4571. PMID 19696410. doi:10.1161/CIRCRESAHA.109.200774. （原始内容存档于2018-08-20）. 
  32. ^ Turunen, Mikko P.; Husso, Tiia; Musthafa, Haja; Laidinen, Svetlana; Dragneva, Galina; Laham-Karam, Nihay; Honkanen, Sanna; Paakinaho, Anne; Laakkonen, Johanna P. Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice. PloS One. 2014, 9 (2): e89979 [2018-08-20]. ISSN 1932-6203. PMC 3935957 可免费查阅. PMID 24587164. doi:10.1371/journal.pone.0089979. （原始内容存档于2018-08-21）. 

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外部連結

检索自“https://zh.wikipedia.org/w/index.php?title=RNA激活&oldid=64455238”