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RNA activation

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RNA activation (RNAa) is a small RNA-guided and Argonaute (Ago)-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. dsRNAs that trigger RNAa have been termed small activating RNA (saRNA).[2] Since the initial discovery of RNAa in human cells, many other groups have made similar observations in different mammalian species including human, non-human primates, rat and mice,[3][4][5][6] plant [7] and C. elegans,[8][9] suggesting that RNAa is an evolutionarily conserved mechanism of gene regulation.

RNAa can be generally classified into two categories: exogenous and endogenous. Exogenous RNAa is triggered by artificially designed saRNAs which target non-coding sequences such as the promoter[1] and the 3’ terminus [10] of a gene and these saRNAs can be chemically synthesized [1] or expressed as short hairpin RNA (shRNA).[4] Whereas for endogenous RNAa, upregulation of gene expression is guided by naturally occurring endogenous small RNAs such as miRNA in mammalian cells [11][12] and C. elegans,[9] and 22G RNA in C. elegans.[8]  

Mechanism

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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][13] but possesses kinetics distinct from RNAi.[14] In contrast to RNAi, promoter-targeted saRNAs induce prolonged activation of gene expression associated with epigenetic changes.[15] 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[6][13] or the chromosomal DNA.[15][16] The RNA-loaded Ago then recruits other proteins such as RHA, also known as nuclear DNA helicase II, and CTR9 to form an RNA-induced transcriptional activation (RITA) complex. RITA can directly interacts with RNAP II to stimulate transcription initiation and productive transcription elongation which is related to increased ubiquitination of H2B.[17][18]

Endogenous RNAa

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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).[11] 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.[12] Since then, a number of miRNAs have been shown to upregulate gene expression by targeting gene promoters [19][20][21][22] or enhancers,[23] thereby, exerting important biological roles. A good example is miR-551b-3p which is overexpressed in ovarian cancer due to amplification.[21] By targeting the promoter of STAT3 to increase its transcription, miR-551b-3p confers to ovarian cancer cells resistance to apoptosis and a proliferative advantage.[21]

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]

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.[24][25]

It is currently unknown how widespread gene regulation by endogenous RNAa is in mammalian cells. Studies have shown that both miRNAs [26] and Ago proteins (Ago1) [27] bind to numerous sites in human genome, especially promoter regions, to exert a largely positive effect on gene transcription.    

Applications

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RNAa has been used to study gene function in lieu of vector-based gene overexpression.[28] Studies have demonstrated RNAa in vivo and its potential therapeutic applications in treating cancer and non-cancerous diseases.[4][29][30][31][32][33][34][35]

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.[36][37]

References

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  1. ^ a b c d e Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S, Enokida H, Dahiya R (November 2006). "Small dsRNAs induce transcriptional activation in human cells". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17337–42. Bibcode:2006PNAS..10317337L. doi:10.1073/pnas.0607015103. PMC 1859931. PMID 17085592.[non-primary source needed]
  2. ^ Li, Longcheng; Dahiya, Rajvir. "Small Activating RNA Molecules and Methods of Use." U.S. Patent US 8,877,721 filed October 1, 2004, and issued November 4, 2014.
  3. ^ Janowski BA, Younger ST, Hardy DB, Ram R, Huffman KE, Corey DR (March 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.
  4. ^ a b c Turunen MP, Lehtola T, Heinonen SE, Assefa GS, Korpisalo P, Girnary R, Glass CK, Väisänen S, Ylä-Herttuala S (September 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.
  5. ^ Huang V, Qin Y, Wang J, Wang X, Place RF, Lin G, Lue TF, Li LC (January 2010). Jin DY (ed.). "RNAa is conserved in mammalian cells". PLOS ONE. 5 (1): e8848. Bibcode:2010PLoSO...5.8848H. doi:10.1371/journal.pone.0008848. PMC 2809750. PMID 20107511.
  6. ^ a b Matsui M, Sakurai F, Elbashir S, Foster DJ, Manoharan M, Corey DR (December 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. PMID 21168770.
  7. ^ Shibuya K, Fukushima S, Takatsuji H (February 2009). "RNA-directed DNA methylation induces transcriptional activation in plants". Proceedings of the National Academy of Sciences of the United States of America. 106 (5): 1660–5. Bibcode:2009PNAS..106.1660S. doi:10.1073/pnas.0809294106. PMC 2629447. PMID 19164525.
  8. ^ a b Seth M, Shirayama M, Gu W, Ishidate T, Conte D, Mello CC (December 2013). "The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression". Developmental Cell. 27 (6): 656–63. doi:10.1016/j.devcel.2013.11.014. PMC 3954781. PMID 24360782.
  9. ^ a b c Turner MJ, Jiao AL, Slack FJ (Jan 7, 2014). "Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans". Cell Cycle. 13 (5): 772–81. doi:10.4161/cc.27679. PMC 3979913. PMID 24398561.
  10. ^ Yue X, Schwartz JC, Chu Y, Younger ST, Gagnon KT, Elbashir S, Janowski BA, Corey DR (August 2010). "Transcriptional regulation by small RNAs at sequences downstream from 3' gene termini". Nature Chemical Biology. 6 (8): 621–9. doi:10.1038/nchembio.400. PMC 3909968. PMID 20581822.
  11. ^ a b Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R (February 2008). "MicroRNA-373 induces expression of genes with complementary promoter sequences". Proceedings of the National Academy of Sciences of the United States of America. 105 (5): 1608–13. Bibcode:2008PNAS..105.1608P. doi:10.1073/pnas.0707594105. PMC 2234192. PMID 18227514. (Erratum: doi:10.1073/pnas.1803343115, PMID 29555737,  Retraction Watch. If the erratum has been checked and does not affect the cited material, please replace {{erratum|...}} with {{erratum|...|checked=yes}}.)[non-primary source needed]
  12. ^ a b Huang V, Place RF, Portnoy V, Wang J, Qi Z, Jia Z, Yu A, Shuman M, Yu J, Li LC (February 2012). "Upregulation of Cyclin B1 by miRNA and its implications in cancer". Nucleic Acids Research. 40 (4): 1695–707. doi:10.1093/nar/gkr934. PMC 3287204. PMID 22053081.[non-primary source needed]
  13. ^ a b Chu Y, Yue X, Younger ST, Janowski BA, Corey DR (November 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.
  14. ^ Li, Long-Cheng (2008). "Small RNA-mediated gene activation". In Morris, Kevin V (ed.). RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. pp. 189–99. ISBN 978-1-904455-25-7.
  15. ^ a b Portnoy V, Huang V, Place RF, Li LC (2011). "Small RNA and transcriptional upregulation". Wiley Interdisciplinary Reviews: RNA. 2 (5): 748–60. doi:10.1002/wrna.90. PMC 3154074. PMID 21823233.
  16. ^ Meng X, Jiang Q, Chang N, Wang X, Liu C, Xiong J, Cao H, Liang Z (March 2016). "Small activating RNA binds to the genomic target site in a seed-region-dependent manner". Nucleic Acids Research. 44 (5): 2274–82. doi:10.1093/nar/gkw076. PMC 4797303. PMID 26873922.
  17. ^ Portnoy V, Lin SH, Li KH, Burlingame A, Hu ZH, Li H, Li LC (March 2016). "saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription". Cell Research. 26 (3): 320–35. doi:10.1038/cr.2016.22. PMC 4783471. PMID 26902284.
  18. ^ Voutila J, Reebye V, Roberts TC, Protopapa P, Andrikakou P, Blakey DC, Habib R, Huber H, Saetrom P, Rossi JJ, Habib NA (December 2017). "Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer". Molecular Therapy. 25 (12): 2705–2714. doi:10.1016/j.ymthe.2017.07.018. PMC 5768526. PMID 28882451.
  19. ^ Matsui M, Chu Y, Zhang H, Gagnon KT, Shaikh S, Kuchimanchi S, Manoharan M, Corey DR, Janowski BA (December 2013). "Promoter RNA links transcriptional regulation of inflammatory pathway genes". Nucleic Acids Research. 41 (22): 10086–109. doi:10.1093/nar/gkt777. PMC 3905862. PMID 23999091.
  20. ^ Dharap A, Pokrzywa C, Murali S, Pandi G, Vemuganti R (2013). "MicroRNA miR-324-3p induces promoter-mediated expression of RelA gene". PLOS ONE. 8 (11): e79467. Bibcode:2013PLoSO...879467D. doi:10.1371/journal.pone.0079467. PMC 3827167. PMID 24265774.
  21. ^ a b c Chaluvally-Raghavan P, Jeong KJ, Pradeep S, Silva AM, Yu S, Liu W, Moss T, Rodriguez-Aguayo C, Zhang D, Ram P, Liu J, Lu Y, Lopez-Berestein G, Calin GA, Sood AK, Mills GB (May 2016). "Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer". Cell Reports. 15 (7): 1493–1504. doi:10.1016/j.celrep.2016.04.034. PMC 4914391. PMID 27160903.
  22. ^ Li S, Wang C, Yu X, Wu H, Hu J, Wang S, Ye Z (January 2017). "miR-3619-5p inhibits prostate cancer cell growth by activating CDKN1A expression". Oncology Reports. 37 (1): 241–248. doi:10.3892/or.2016.5250. PMID 27878260.
  23. ^ Xiao M, Li J, Li W, Wang Y, Wu F, Xi Y, Zhang L, Ding C, Luo H, Li Y, Peng L, Zhao L, Peng S, Xiao Y, Dong S, Cao J, Yu W (October 2017). "MicroRNAs activate gene transcription epigenetically as an enhancer trigger". RNA Biology. 14 (10): 1326–1334. doi:10.1080/15476286.2015.1112487. PMC 5711461. PMID 26853707.
  24. ^ Conine CC, Moresco JJ, Gu W, Shirayama M, Conte D, Yates JR, Mello CC (December 2013). "Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans". Cell. 155 (7): 1532–44. doi:10.1016/j.cell.2013.11.032. PMC 3924572. PMID 24360276.
  25. ^ Wedeles CJ, Wu MZ, Claycomb JM (December 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.
  26. ^ Paugh SW, Coss DR, Bao J, Laudermilk LT, Grace CR, Ferreira AM, Waddell MB, Ridout G, Naeve D, Leuze M, LoCascio PF, Panetta JC, Wilkinson MR, Pui CH, Naeve CW, Uberbacher EC, Bonten EJ, Evans WE (February 2016). "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. 12 (2): e1004744. Bibcode:2016PLSCB..12E4744P. doi:10.1371/journal.pcbi.1004744. PMC 4742280. PMID 26844769.
  27. ^ Huang V, Zheng J, Qi Z, Wang J, Place RF, Yu J, Li H, Li LC (2013). "Ago1 Interacts with RNA polymerase II and binds to the promoters of actively transcribed genes in human cancer cells". PLOS Genetics. 9 (9): e1003821. doi:10.1371/journal.pgen.1003821. PMC 3784563. PMID 24086155.
  28. ^ Wang J, Place RF, Huang V, Wang X, Noonan EJ, Magyar CE, Huang J, Li LC (December 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.
  29. ^ Chen R, Wang T, Rao K, Yang J, Zhang S, Wang S, Liu J, Ye Z (October 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.
  30. ^ Kang MR, Yang G, Place RF, Charisse K, Epstein-Barash H, Manoharan M, Li LC (October 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.
  31. ^ Place RF, Wang J, Noonan EJ, Meyers R, Manoharan M, Charisse K, Duncan R, Huang V, Wang X, Li LC (March 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. PMC 3381590. PMID 23343884.
  32. ^ Yoon S, Huang KW, Reebye V, Mintz P, Tien YW, Lai HS, Sætrom P, Reccia I, Swiderski P, Armstrong B, Jozwiak A, Spalding D, Jiao L, Habib N, Rossi JJ (June 2016). "Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo". Molecular Therapy. 24 (6): 1106–1116. doi:10.1038/mt.2016.60. PMC 4923325. PMID 26983359.
  33. ^ Huan H, Wen X, Chen X, Wu L, Liu W, Habib NA, Bie P, Xia F (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. Bibcode:2016PLoSO..1153117H. doi:10.1371/journal.pone.0153117. PMC 4822802. PMID 27050434.
  34. ^ Li C, Jiang W, Hu Q, Li LC, Dong L, Chen R, Zhang Y, Tang Y, Thrasher JB, Liu CB, Li B (April 2016). "Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis". Oncotarget. 7 (16): 22893–910. doi:10.18632/oncotarget.8290. PMC 5008410. PMID 27014974.
  35. ^ Reebye V, Huang KW, Lin V, Jarvis S, Cutilas P, Dorman S, Ciriello S, Andrikakou P, Voutila J, Saetrom P, Mintz PJ, Reccia I, Rossi JJ, Huber H, Habib R, Kostomitsopoulos N, Blakey DC, Habib NA (June 2018). "Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer". Oncogene. 37 (24): 3216–3228. doi:10.1038/s41388-018-0126-2. PMC 6013054. PMID 29511346.
  36. ^ "MiNA Therapeutics Announces Initiation of Phase I Clinical Study of MTL-CEBPA in Patients with Liver Cancer | Business Wire". www.businesswire.com. 2 June 2016. Retrieved 2016-06-06.
  37. ^ "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

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