RNA activation

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RNA activation (RNAa) is a small RNA-guided and Argonaute-dependent gene regulation phenomenon in which promoter-targeted short double-stranded RNAs (dsRNAs) induce target gene expression at the transcriptional/epigenetic level. RNAa was first reported in a 2006 PNAS paper by Li et al.[1] who also coined the term "RNAa" as a contrast to RNA interference (RNAi)[1] to describe such gene activation phenomenon. Soon after, several groups made similar observation in different mammalian species including human, non-human primates, rat and mice,[2][3][4][5] suggesting that RNAa is a general gene regulation mechanism conserved at least in mammals. In these studies, upregulation of gene expression is achieved by targeting selected promoter regions using either synthetic 21-nucleotide dsRNAs or vector expressed small hairpin RNAs (shRNAs). Such promoter targeted dsRNAs have been termed antigene RNA (agRNAs)[5] or small activating RNA (saRNA).[1][6]

Similar gene activation mechanisms mediated by Argonaute-small RNAs have also been observed in plants [7] and C. elegans.[8][9]

Mechanism of RNAa[edit]

The molecular mechanism of RNAa is not fully understood. Similar to RNAi, it has been shown that mammalian RNAa requires members of the Ago clade of Argonaute proteins, particularly Ago2,[1][10] but possesses kinetics distinct from RNAi.[11] In contrast to RNAi, promoter-targeted agRNAs induce prolonged activation of gene expression associated with epigenetic changes.[12] It is currently suggested that saRNAs are first loaded and processed by an Ago protein to form an Ago-RNA complex which is then guided by the RNA to its promoter target. The target can be a non-coding transcript overlapping the promoter[5][10] or the chromosomal DNA.[12] Ago then recruits histone modifying enzymes such as histone methyltransferase to the promoter to activate transcription by causing permissive epigenetic changes.[13]

Endogenous RNAa[edit]

In 2008, Place et al. identified targets for miRNA miR-373 on the promoters of several human genes and found that introduction of miR-373 mimics into human cells induced the expression of its predicted target genes. This study provided the first example that RNAa could be mediated by naturally occurring non-coding RNA (ncRNA).[14] In 2011, Huang et al. further demonstrated in mouse cells that endogenous RNAa mediated by miRNAs functions in a physiological context and is possibly exploited by cancer cells to gain a growth advantage.[15]

In C. elegans, Argonaute CSR-1 interacts with 22G small RNAs derived from RNA-dependent RNA polymerase and antisense to germline-expressed transcripts to protect these mRNAs from Piwi-piRNA mediated silencing via promoting epigenetic activation.[16][17] In C. elegans hypodermal seam cells, the transcription of lin-4 miRNA is positively regulated by lin-4 itself which binds to a conserved lin-4 complementary element in its promoter, constituting a positive autoregulatory loop.[9]

Applications of RNAa[edit]

RNAa has been used to study gene function in lieu of vector-based gene overexpression.[18] Studies have demonstrated RNAa in vivo and its potential therapeutic applications in treating cancer and non-cancerous diseases.[3][19][20][21][22][23][24]

In June 2016, UK-based MiNA Therapeutics announced the initiation of a phase I trial of the first-ever saRNA drug MTL-CEBPA in patients with liver cancer, in an attempt to activate CEBPA gene.[25][26]


  1. ^ a b c d Li, Long-Cheng; Okino, Steven T.; Zhao, Hong; Pookot, Deepa; Place, Robert F.; Urakami, Shinji; Enokida, Hideki; Dahiya, Rajvir (2006). "Small dsRNAs induce transcriptional activation in human cells". Proceedings of the National Academy of Sciences. 103 (46): 17337–42. PMC 1859931Freely accessible. PMID 17085592. doi:10.1073/pnas.0607015103. [non-primary source needed]
  2. ^ Janowski, Bethany A; Younger, Scott T; Hardy, Daniel B; Ram, Rosalyn; Huffman, Kenneth E; Corey, David R (2007). "Activating gene expression in mammalian cells with promoter-targeted duplex RNAs". Nature Chemical Biology. 3 (3): 166–73. PMID 17259978. doi:10.1038/nchembio860. 
  3. ^ a b Turunen, Mikko P.; Lehtola, Tiia; Heinonen, Suvi E.; Assefa, Genet S.; Korpisalo, Petra; Girnary, Roseanne; Glass, Christopher K.; Väisänen, Sami; Ylä-Herttuala, Seppo (2009). "Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism: A Novel Example of Epigenetherapy". Circulation Research. 105 (6): 604–9. PMID 19696410. doi:10.1161/CIRCRESAHA.109.200774. 
  4. ^ Huang, Vera; Qin, Yi; Wang, Ji; Wang, Xiaoling; Place, Robert F.; Lin, Guiting; Lue, Tom F.; Li, Long-Cheng (2010). Jin, Dong-Yan, ed. "RNAa is Conserved in Mammalian Cells". PLoS ONE. 5 (1): e8848. PMC 2809750Freely accessible. PMID 20107511. doi:10.1371/journal.pone.0008848. 
  5. ^ a b c Matsui, Masayuki; Sakurai, Fuminori; Elbashir, Sayda; Foster, Donald J.; Manoharan, Muthiah; Corey, David R. (2010). "Activation of LDL Receptor Expression by Small RNAs Complementary to a Noncoding Transcript that Overlaps the LDLR Promoter". Chemistry & Biology. 17 (12): 1344–55. PMC 3071588Freely accessible. PMID 21168770. doi:10.1016/j.chembiol.2010.10.009. 
  6. ^ Voutila, J; Sætrom, P; Mintz, P; Sun, G; Alluin, J; Rossi, JJ; Habib, NA; Kasahara, N (Aug 7, 2012). "Gene Expression Profile Changes After Short-activating RNA-mediated Induction of Endogenous Pluripotency Factors in Human Mesenchymal Stem Cells.". Molecular Therapy: Nucleic Acids. 1 (8): e35. PMC 3437803Freely accessible. PMID 23344177. doi:10.1038/mtna.2012.20. 
  7. ^ Shibuya, Kenichi; Fukushima, Setsuko; Takatsuji, Hiroshi (2009). "RNA-directed DNA methylation induces transcriptional activation in plants". Proceedings of the National Academy of Sciences. 106 (5): 1660–5. PMC 2629447Freely accessible. PMID 19164525. doi:10.1073/pnas.0809294106. 
  8. ^ Seth, Meetu; Shirayama, Masaki; Gu, Weifeng; Ishidate, Takao; Conte, Darryl; Mello, Craig C. (2013-12-23). "The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression". Developmental Cell. 27 (6): 656–663. ISSN 1878-1551. PMC 3954781Freely accessible. PMID 24360782. doi:10.1016/j.devcel.2013.11.014. 
  9. ^ a b Turner, MJ; Jiao, AL; Slack, FJ (Jan 7, 2014). "Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans.". Cell cycle (Georgetown, Tex.). 13 (5): 772–81. PMID 24398561. doi:10.4161/cc.27679. 
  10. ^ a b Chu, Yongjun; Yue, Xuan; Younger, Scott T.; Janowski, Bethany A.; Corey, David R. (2010). "Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter". Nucleic Acids Research. 38 (21): 7736–48. PMC 2995069Freely accessible. PMID 20675357. doi:10.1093/nar/gkq648. 
  11. ^ Li, Long-Cheng (2008). "Small RNA-mediated gene activation". In Morris, Kevin V. RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. pp. 189–99. ISBN 978-1-904455-25-7. 
  12. ^ a b Portnoy, Victoria; Huang, Vera; Place, Robert F.; Li, Long-Cheng (2011). "Small RNA and transcriptional upregulation". Wiley Interdisciplinary Reviews: RNA. 2 (5): 748–60. PMC 3154074Freely accessible. PMID 21823233. doi:10.1002/wrna.90. 
  13. ^ Portnoy, Victoria; Lin, Szu Hua Sharon; Li, Kathy H.; Burlingame, Alma; Hu, Zheng-Hui; Li, Hao; Li, Long-Cheng (2016-03-01). "saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription". Cell Research. 26 (3): 320–335. ISSN 1748-7838. PMC 4783471Freely accessible. PMID 26902284. doi:10.1038/cr.2016.22. 
  14. ^ Place, Robert F.; Li, Long-Cheng; Pookot, Deepa; Noonan, Emily J.; Dahiya, Rajvir (2008). "MicroRNA-373 induces expression of genes with complementary promoter sequences". Proceedings of the National Academy of Sciences. 105 (5): 1608–13. PMC 2234192Freely accessible. PMID 18227514. doi:10.1073/pnas.0707594105. [non-primary source needed]
  15. ^ Huang, Vera; Place, Robert F.; Portnoy, Victoria; Wang, Ji; Qi, Zhongxia; Jia, Zhejun; Yu, Angela; Shuman, Marc; et al. (2011). "Upregulation of Cyclin B1 by miRNA and its implications in cancer". Nucleic Acids Research. 40 (4): 1695–707. PMC 3287204Freely accessible. PMID 22053081. doi:10.1093/nar/gkr934. [non-primary source needed]
  16. ^ Conine, Colin C.; Moresco, James J.; Gu, Weifeng; Shirayama, Masaki; Conte, Darryl; Yates, John R.; Mello, Craig C. (2013-12-19). "Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans". Cell. 155 (7): 1532–1544. ISSN 1097-4172. PMC 3924572Freely accessible. PMID 24360276. doi:10.1016/j.cell.2013.11.032. 
  17. ^ Wedeles, CJ; Wu, MZ; Claycomb, JM (Dec 18, 2013). "Protection of Germline Gene Expression by the C. elegans Argonaute CSR-1.". Developmental Cell. 27 (6): 664–71. PMID 24360783. doi:10.1016/j.devcel.2013.11.016. 
  18. ^ Wang, Ji; Place, Robert F.; Huang, Vera; Wang, Xiaoling; Noonan, Emily J.; Magyar, Clara E.; Huang, Jiaoti; Li, Long-Cheng (2010). "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. 70 (24): 10182–91. PMC 3076047Freely accessible. PMID 21159640. doi:10.1158/0008-5472.CAN-10-2414. 
  19. ^ Chen, Ruibao; Wang, Tao; Rao, Ke; Yang, Jun; Zhang, Shilin; Wang, Shaogang; Liu, Jihong; Ye, Zhangqun (2011). "Up-regulation of VEGF by Small Activator RNA in Human Corpus Cavernosum Smooth Muscle Cells". The Journal of Sexual Medicine. 8 (10): 2773–80. PMID 21819543. doi:10.1111/j.1743-6109.2011.02412.x. 
  20. ^ Kang, MR; Yang, G; Place, RF; Charisse, K; Epstein-Barash, H; Manoharan, M; Li, LC (Oct 1, 2012). "Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth.". Cancer Research. 72 (19): 5069–79. PMID 22869584. doi:10.1158/0008-5472.can-12-1871. 
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  22. ^ Yoon, Sorah; Huang, Kai-Wen; Reebye, Vikash; Mintz, Paul; Tien, Yu-Wen; Lai, Hong-Shiee; Sætrom, Pål; Reccia, Isabella; Swiderski, Piotr (2016-03-17). "Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo". Molecular Therapy. 24: 1106–16. ISSN 1525-0024. PMC 4923325Freely accessible. PMID 26983359. doi:10.1038/mt.2016.60. 
  23. ^ Huan, Hongbo; Wen, Xudong; Chen, Xuejiao; Wu, Lili; Liu, Weihui; Habib, Nagy A.; Bie, Ping; Xia, Feng (2016-01-01). "C/EBPα Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/β-Catenin Signaling Mediated EMT". PloS One. 11 (4): e0153117. ISSN 1932-6203. PMC 4822802Freely accessible. PMID 27050434. doi:10.1371/journal.pone.0153117. 
  24. ^ Li, Changlin; Jiang, Wencong; Hu, Qingting; Li, Long-Cheng; Dong, Liang; Chen, Ruibao; Zhang, Yinghong; Tang, Yuzhe; Thrasher, J. Brantley (2016-03-23). "Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis". Oncotarget. 7: 22893–910. ISSN 1949-2553. PMID 27014974. doi:10.18632/oncotarget.8290. 
  25. ^ "MiNA Therapeutics Announces Initiation of Phase I Clinical Study of MTL-CEBPA in Patients with Liver Cancer | Business Wire". www.businesswire.com. Retrieved 2016-06-06. 
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