RNA activation

RNA activation (RNAa) is a small RNA-guided gene regulation phenomenon in which promoter-targeted short double-stranded RNA (dsRNA) induces target gene expression at the transcriptional 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]

Similar dsRNA-mediated gene activation phenomenon has also been observed in plants.[6]

Contents

Mechanism of RNAa

The molecular mechanism of RNAa is not fully understood. Similar to RNAi, It has been shown that RNAa requires an evolutionarily conserved family of Argonaute (Ago) proteins, particularly Ago2,[1][7] but possesses kinetics distinct from RNAi.[8] In contrast to RNAi, promoter-targeted agRNAs induce prolonged activation of gene expression associated with epigenetic changes.[9] It is currently suggested that agRNA is first loaded and processed by an Ago protein which then guides it to its promoter target, which can be a non-coding transcript overlapping the promoter[7][5] or the chromosomal DNA.[9] Ago then recruits histone modifying enzymes such as histone methyltransferase to the promoter to activate transcription by causing permissive epigenetic changes.

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).[10] 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.[11]

Applications of RNAa

RNAa has been used to study gene function in lieu of vector-based gene overexpression.[12] Studies have demonstrated RNAa in vivo and its potential therapeutic applications.[3][13]

References

  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. doi:10.1073/pnas.0607015103. PMC 1859931. PMID 17085592. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1859931. 
  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. ^ a b Turunen, Mikko P.; Lehtola, Tiia; Heinonen, Suvi E.; Assefa, Genet S.; Korpisalo, Petra; Girnary, Roseanne; Glass, Christopher K.; Väisänen, Sami et al. (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 2809750. PMID 20107511. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2809750. 
  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. doi:10.1016/j.chembiol.2010.10.009. PMC 3071588. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3071588. 
  6. ^ 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 2629447. PMID 19164525. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2629447. 
  7. ^ 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. doi:10.1093/nar/gkq648. PMC 2995069. PMID 20675357. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2995069. 
  8. ^ 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. http://books.google.com/books?id=r67Lrf9r9XEC&pg=PA189. 
  9. ^ 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. doi:10.1002/wrna.90. PMC 3154074. PMID 21823233. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3154074. 
  10. ^ 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 2234192. PMID 18227514. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2234192. 
  11. ^ 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. doi:10.1093/nar/gkr934. 
  12. ^ 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 3076047. PMID 21159640. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3076047. 
  13. ^ 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. 

Further reading

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