RNA激活

RNA激活（RNA activation, RNAa) 是一種由小分子RNA介導的特異性基因表達上調機制，是李龍承等^[1]於2006年首先在人細胞中發現並命名的。隨後，其他研究小組也報道了相似的現象，證明了RNA激活是從人及大小鼠等哺乳類動物到植物及線蟲中的保守現象^[2]^[3]^[4]^[5]^[6]^[7]^[8]^[9]^[10]。RNA激活是由靶向基因啟動子區域的雙鏈小RNA（dsRNA）分子介導並需要Argonaute（AGO）蛋白的參與^[1]^[11]。這類能夠誘導RNA激活現象（即激活基因表達）的dsRNA被稱為小激活RNA（small activating RNA，saRNA）^[12]。saRNA可通過人工設計及化學合成而獲得，也可為天然存在的內源性RNA如miRNA；前者介導的RNA激活被稱為外源性RNA激活，後者為內源性RNA激活。

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與RNA干擾（RNAi）的異同

介導外源性RNA激活的saRNA與介導RNAi的siRNA結構相似，是含21個核苷酸的雙鏈RNA（dsRNA），其兩條鏈在各自的3』端含2個核苷酸的突出。和RNAi一樣，RNAa也需要AGO蛋白特別是AGO2的參與，其作用可能是處理和活化saRNA分子，並介導saRNA與其啟動子上的靶位點結合。與RNAi（主要發生在胞漿）不同的是，RNA激活機製發生在細胞核，介導RNA激活的saRNA靶向啟動子而不是mRNA序列，此外，RNA激活具有特殊的時效性，表現為其效果（基因表達上調）的出現呈現48小時左右的滯後，及效果的長久性（10-14天）^[1]^[13]^[14]。其機制被認為是因為RNA激活導致了表觀遺傳的改變^[15]。

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內源性RNA激活

2008年Place等^[16]報道了天然存在的miRNA也能夠靶向啟動子序列而誘導RNA激活。他們發現人CDH1及CSDC2基因啟動子存在miR-373的靶位點，在人腫瘤細胞中引入miR-373的模擬物（mimics）能激活其靶基因的表達。後來，Huang等進一步證實了內源性miRNA介導的RNAa，並且發現該機制在正常及腫瘤細胞的增殖中起重要作用^[17]。Xiao等還報道了靶向增強子區域的miRNA也能夠誘導RNA激活^[18]。Chaluvally-Raghavan等發現miR-551b-3p通過靶向激活STAT3而促進卵巢癌細胞增殖、生存和腫瘤生長^[19]。目前對於有多少基因受到內源性RNA激活機制的調控還不清楚，但有研究發現miRNA^[20]及AGO蛋白^[21]在人基因組的啟動子區存在廣泛的結合位點，提示miRNA可能在轉錄或者表觀遺傳水平調控大量的基因。

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RNA激活的應用

RNA激活是一種簡單易行的上調基因表達的方法，在生物醫學領域具有廣泛的潛在用途，包括作為工具用於研究基因的功能^[22]和對細胞進行重新編程^[23]^[24]^[25]^[26]，以及作為治療疾病的手段，包括腫瘤、心血管疾病、勃起功能障礙等^[27]^[28]^[29]^[30]^[31]^[32]。目前，治療肝癌的saRNA藥已經進入臨床試驗^[28]。

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參考來源

[1]
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 . 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. （原始內容存檔於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 . PMID 20107511. doi:10.1371/journal.pone.0008848. （原始內容存檔於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]. （原始內容存檔於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 . PMID 26873922. doi:10.1093/nar/gkw076. （原始內容存檔於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 . PMID 19164525. doi:10.1073/pnas.0809294106. （原始內容存檔於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 . PMID 24360782. doi:10.1016/j.devcel.2013.11.014. （原始內容存檔於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 . PMID 24398561. doi:10.4161/cc.27679. （原始內容存檔於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 . PMID 26902284. doi:10.1038/cr.2016.22. （原始內容存檔於2018-08-21）. 請檢查|date=中的日期值 (幫助)
[12]
Small Activating RNA Molecules and Methods of Use, 2014-10-01 [2018-08-20], （原始內容存檔於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 . PMID 20662764. （原始內容存檔於2018-08-21）. 請檢查|date=中的日期值 (幫助)
[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 . PMID 23929703. doi:10.1002/hep.26669. （原始內容存檔於2018-08-20）. 請檢查|date=中的日期值 (幫助)
[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. （原始內容存檔於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]. （原始內容存檔於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]. （原始內容存檔於2014-06-07）. 請檢查|date=中的日期值 (幫助)
[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. （原始內容存檔於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 . PMID 27160903. doi:10.1016/j.celrep.2016.04.034. （原始內容存檔於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 . PMID 26844769. doi:10.1371/journal.pcbi.1004744. （原始內容存檔於2018-08-20）. 請檢查|date=中的日期值 (幫助)
[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 . PMID 24086155. doi:10.1371/journal.pgen.1003821. （原始內容存檔於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 . PMID 21159640. doi:10.1158/0008-5472.CAN-10-2414. （原始內容存檔於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 . PMID 25232932. doi:10.1089/scd.2014.0290. （原始內容存檔於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 . PMID 22339500. doi:10.1042/BJ20111491. （原始內容存檔於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. （原始內容存檔於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 . PMID 23736775. doi:10.1038/mtna.2013.23. （原始內容存檔於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. （原始內容存檔於2018-08-20）.
[28]
First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov. [2018-08-20]. （原始內容存檔於2018-08-20）（英語）.
[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. （原始內容存檔於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 . PMID 28882451. doi:10.1016/j.ymthe.2017.07.018. （原始內容存檔於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. （原始內容存檔於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 . PMID 24587164. doi:10.1371/journal.pone.0089979. （原始內容存檔於2018-08-21）.

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延伸閱讀

Check, Erika. RNA interference: Hitting the on switch. Nature. 2007, 448 (7156): 855–8. PMID 17713502. doi:10.1038/448855a.
Long-Cheng Li. RNA Activation. Singapore: Springer Nature. 2017 [2018-08-20]. ISBN 978-981-10-4310-9. （原始內容存檔於2018-08-20）.
Garber K. Genetics. Small RNAs reveal an activating side. Science. November 2006, 314 (5800): 741–2 [2011-12-13]. PMID 17082428. doi:10.1126/science.314.5800.741a. （原始內容存檔於2008-06-19）.
How to get your genes switched on. New Scientist 16 November 2006（頁面存檔備份，存於網際網路檔案館）

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外部連結

RNAa FAQs Li Lab, University of California San Francisco（頁面存檔備份，存於網際網路檔案館）
saRNAdb - Resource of small activating RNAs for up-regulating gene expression IMTech（頁面存檔備份，存於網際網路檔案館）

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[pnas-1] [1]
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 . PMID 17085592. doi:10.1073/pnas.0607015103.

[ncb-2] [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.

[LiLC-3] [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. （原始內容存檔於2012-01-02）.

[4] [4]
Check E. RNA interference: hitting the on switch. Nature. 2007, 448 (7156): 855–8. PMID 17713502. doi:10.1038/448855a.

[5] [5]
Huang V; et al. RNAa is conserved in mammalian cells. PLoS One. 2010, 5 (1): e8848 [2011-12-13]. PMC 2809750 . PMID 20107511. doi:10.1371/journal.pone.0008848. （原始內容存檔於2011-08-14）.

[circRes-6] [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]. （原始內容存檔於2014-10-21）.

[7] [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 . PMID 26873922. doi:10.1093/nar/gkw076. （原始內容存檔於2018-08-20）.

[8] [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 . PMID 19164525. doi:10.1073/pnas.0809294106. （原始內容存檔於2018-08-21）.

[9] [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 . PMID 24360782. doi:10.1016/j.devcel.2013.11.014. （原始內容存檔於2018-08-21）.

[10] [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 . PMID 24398561. doi:10.4161/cc.27679. （原始內容存檔於2018-08-20）.

[11] [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 . PMID 26902284. doi:10.1038/cr.2016.22. （原始內容存檔於2018-08-21）. 請檢查|date=中的日期值 (幫助)

[12] [12]
Small Activating RNA Molecules and Methods of Use, 2014-10-01 [2018-08-20], （原始內容存檔於2019-02-17）

[13] [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 . PMID 20662764. （原始內容存檔於2018-08-21）. 請檢查|date=中的日期值 (幫助)

[14] [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 . PMID 23929703. doi:10.1002/hep.26669. （原始內容存檔於2018-08-20）. 請檢查|date=中的日期值 (幫助)

[WIREsRNA-15] [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. （原始內容存檔於2015-05-26）.

[16] [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]. （原始內容存檔於2012-06-01）.

[17] [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]. （原始內容存檔於2014-06-07）. 請檢查|date=中的日期值 (幫助)

[18] [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. （原始內容存檔於2018-08-20）.

[19] [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 . PMID 27160903. doi:10.1016/j.celrep.2016.04.034. （原始內容存檔於2018-08-20）.

[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 . PMID 26844769. doi:10.1371/journal.pcbi.1004744. （原始內容存檔於2018-08-20）. 請檢查|date=中的日期值 (幫助)

[21] [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 . PMID 24086155. doi:10.1371/journal.pgen.1003821. （原始內容存檔於2018-08-20）.

[22] [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 . PMID 21159640. doi:10.1158/0008-5472.CAN-10-2414. （原始內容存檔於2018-08-20）.

[23] [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 . PMID 25232932. doi:10.1089/scd.2014.0290. （原始內容存檔於2018-08-20）.

[24] [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 . PMID 22339500. doi:10.1042/BJ20111491. （原始內容存檔於2018-08-20）.

[25] [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. （原始內容存檔於2018-08-21）.

[26] [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 . PMID 23736775. doi:10.1038/mtna.2013.23. （原始內容存檔於2018-08-20）.

[27] [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. （原始內容存檔於2018-08-20）.

[:0-28] [28]
First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov. [2018-08-20]. （原始內容存檔於2018-08-20）（英語）.

[29] [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. （原始內容存檔於2018-08-21）.

[30] [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 . PMID 28882451. doi:10.1016/j.ymthe.2017.07.018. （原始內容存檔於2018-08-20）.

[31] [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. （原始內容存檔於2018-08-20）.

[32] [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 . PMID 24587164. doi:10.1371/journal.pone.0089979. （原始內容存檔於2018-08-21）.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]