RNA activation

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

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

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

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]

References

  1. 1 2 3 4 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. doi:10.1073/pnas.0607015103. PMC 1859931Freely accessible. PMID 17085592.
  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. doi:10.1038/nchembio860. PMID 17259978.
  3. 1 2 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. doi:10.1161/CIRCRESAHA.109.200774. PMID 19696410.
  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. doi:10.1371/journal.pone.0008848. PMC 2809750Freely accessible. PMID 20107511.
  5. 1 2 3 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. doi:10.1016/j.chembiol.2010.10.009. PMC 3071588Freely accessible. PMID 21168770.
  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. doi:10.1038/mtna.2012.20. PMC 3437803Freely accessible. PMID 23344177.
  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. doi:10.1073/pnas.0809294106. PMC 2629447Freely accessible. PMID 19164525.
  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. doi:10.1016/j.devcel.2013.11.014. ISSN 1878-1551. PMC 3954781Freely accessible. PMID 24360782.
  9. 1 2 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. doi:10.4161/cc.27679. PMID 24398561.
  10. 1 2 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. doi:10.1093/nar/gkq648. PMC 2995069Freely accessible. PMID 20675357.
  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. 1 2 Portnoy, Victoria; Huang, Vera; Place, Robert F.; Li, Long-Cheng (2011). "Small RNA and transcriptional upregulation". Wiley Interdisciplinary Reviews: RNA. 2 (5): 748–60. doi:10.1002/wrna.90. PMC 3154074Freely accessible. PMID 21823233.
  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. doi:10.1038/cr.2016.22. ISSN 1748-7838. PMC 4783471Freely accessible. PMID 26902284.
  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. doi:10.1073/pnas.0707594105. PMC 2234192Freely accessible. PMID 18227514.
  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. doi:10.1093/nar/gkr934. PMC 3287204Freely accessible. PMID 22053081.
  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. doi:10.1016/j.cell.2013.11.032. ISSN 1097-4172. PMC 3924572Freely accessible. PMID 24360276.
  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. doi:10.1016/j.devcel.2013.11.016. PMID 24360783.
  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. doi:10.1158/0008-5472.CAN-10-2414. PMC 3076047Freely accessible. PMID 21159640.
  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. doi:10.1111/j.1743-6109.2011.02412.x. PMID 21819543.
  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. doi:10.1158/0008-5472.can-12-1871. PMID 22869584.
  21. ↑ Place, RF; Wang, J; Noonan, EJ; Meyers, R; Manoharan, M; Charisse, K; Duncan, R; Huang, V; Wang, X; Li, LC (Mar 27, 2012). "Formulation of Small Activating RNA Into Lipidoid Nanoparticles Inhibits Xenograft Prostate Tumor Growth by Inducing p21 Expression.". Molecular therapy. Nucleic acids. 1 (3): e15. doi:10.1038/mtna.2012.5. PMID 23343884.
  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: The Journal of the American Society of Gene Therapy. 24: 1106–16. doi:10.1038/mt.2016.60. ISSN 1525-0024. PMC 4923325Freely accessible. PMID 26983359.
  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. doi:10.1371/journal.pone.0153117. ISSN 1932-6203. PMC 4822802Freely accessible. PMID 27050434.
  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. doi:10.18632/oncotarget.8290. ISSN 1949-2553. PMID 27014974.
  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.
  26. ↑ "First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-06-06.

Further reading

External links

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