Small activating RNA

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Small activating RNAs (saRNAs) are small double-stranded RNAs (dsRNAs) that target gene promoters to induce transcriptional gene activation in a process known as RNA activation (RNAa).

Contents

Small dsRNAs, such as small interfering RNAs (siRNAs) and microRNAs (miRNAs), are known to be the trigger of an evolutionarily conserved mechanism known as RNA interference (RNAi). RNAi invariably leads to gene silencing via remodeling of chromatin to thereby suppress transcription, degrading complementary mRNA, or blocking protein translation. Later it was found that dsRNAs can also act to activate transcription and was thus designated saRNA. By targeting selected sequences in gene promoters, saRNAs induce target gene expression at the transcriptional/epigenetic level. [1] [2]

saRNAs are typically 21 nucleotides in length with a 2 nucleotide overhang at the 3' end of each strand, the same structure as a typical siRNA. To identify an saRNA that can activate a gene of interest, several saRNAs need to be designed within a 1- to 2-kbp promoter region by following a set of rules [3] [4] and tested in cultured cells. In some reports, saRNAs are designed in such a way to target non-coding transcripts that overlap the promoter sequence of a protein coding gene. [5] [6] Both chemically synthesized saRNAs and saRNAs expressed as short hairpin RNA (shRNA) have been used in in vitro and in vivo experiments.

An online resource for saRNAs has been developed to integrate experimentally verified saRNAs and proteins involved. [7]

Therapeutic use of saRNAs have been suggested. They have been tested in animal models to treat bladder tumors, [8] liver carcinogenesis, [9] [10] pancreatic cancer, [11] and erectile dysfunction. [12]

In 2016, a phase I clinical trial involving advanced liver cancer patients [13] was launched for the saRNA drug MTL-CEBPA. It aimed to complete in 2021. [14]

References

  1. ↑ Li, Long-Cheng; Okino, Steven T.; Zhao, Hong; Pookot, Deepa; Place, Robert F.; Urakami, Shinji; Enokida, Hideki; Dahiya, Rajvir (2006-11-14). "Small dsRNAs induce transcriptional activation in human cells". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17337–17342. Bibcode:2006PNAS..10317337L. doi: 10.1073/pnas.0607015103 . ISSN   0027-8424. PMC   1859931 . PMID   17085592.
  2. ↑ Janowski, Bethany A.; Younger, Scott T.; Hardy, Daniel B.; Ram, Rosalyn; Huffman, Kenneth E.; Corey, David R. (2007-03-01). "Activating gene expression in mammalian cells with promoter-targeted duplex RNAs". Nature Chemical Biology. 3 (3): 166–173. doi:10.1038/nchembio860. ISSN   1552-4450. PMID   17259978. S2CID   10716220.
  3. ↑ Huang, Vera; Qin, Yi; Wang, Ji; Wang, Xiaoling; Place, Robert F.; Lin, Guiting; Lue, Tom F.; Li, Long-Cheng (2010-01-01). "RNAa is conserved in mammalian cells". PLOS ONE. 5 (1): e8848. Bibcode:2010PLoSO...5.8848H. doi: 10.1371/journal.pone.0008848 . ISSN   1932-6203. PMC   2809750 . PMID   20107511.{{cite journal}}: CS1 maint: article number as page number (link)
  4. ↑ Wang, Ji; Place, Robert F.; Portnoy, Victoria; Huang, Vera; Kang, Moo Rim; Kosaka, Mika; Ho, Maurice Kwok Chung; Li, Long-Cheng (2015-03-11). "Inducing gene expression by targeting promoter sequences using small activating RNAs". Journal of Biological Methods. 2 (1): 14. doi:10.14440/jbm.2015.39. ISSN   2326-9901. PMC   4379447 . PMID   25839046.
  5. ↑ Voutila, Jon; Sætrom, Pål; Mintz, Paul; Sun, Guihua; Alluin, Jessica; Rossi, John J; Habib, Nagy A; Kasahara, Noriyuki (2012-08-01). "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. ISSN   2162-2531. PMC   3437803 . PMID   23344177.
  6. ↑ Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Manoharan, Muthiah; Corey, David R.; Janowski, Bethany A. (2013-12-01). "Promoter RNA links transcriptional regulation of inflammatory pathway genes". Nucleic Acids Research. 41 (22): 10086–10109. doi:10.1093/nar/gkt777. ISSN   1362-4962. PMC   3905862 . PMID   23999091.
  7. ↑ Dar, Showkat Ahmad; Kumar, Manoj (July 2018). "saRNAdb: Resource of Small Activating RNAs for Up-regulating the Gene Expression". Journal of Molecular Biology. 430 (15): 2212–2218. doi:10.1016/j.jmb.2018.03.023. PMID   29625201. S2CID   4936884.
  8. ↑ Kang, Moo Rim; Yang, Glen; Place, Robert F.; Charisse, Klaus; Epstein-Barash, Hila; Manoharan, Muthiah; Li, Long-Cheng (2012-10-01). "Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth". Cancer Research. 72 (19): 5069–5079. doi: 10.1158/0008-5472.CAN-12-1871 . ISSN   1538-7445. PMID   22869584.
  9. ↑ Reebye, Vikash; Sætrom, Pål; Mintz, Paul J.; Huang, Kai-Wen; Swiderski, Piotr; Peng, Ling; Liu, Cheng; Liu, Xiaoxuan; Lindkaer-Jensen, Steen (2014-01-01). "Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo". Hepatology. 59 (1): 216–227. doi:10.1002/hep.26669. ISSN   1527-3350. PMC   4655108 . PMID   23929703.
  10. ↑ 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. Bibcode:2016PLoSO..1153117H. doi: 10.1371/journal.pone.0153117 . ISSN   1932-6203. PMC   4822802 . PMID   27050434.{{cite journal}}: CS1 maint: article number as page number (link)
  11. ↑ 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 (6): 1106–16. doi:10.1038/mt.2016.60. ISSN   1525-0024. PMC   4923325 . PMID   26983359.
  12. ↑ Wang, Tao; Li, Mingchao; Yuan, Huixin; Zhan, Yin; Xu, Hua; Wang, Shaogang; Yang, Weiming; Liu, Jihong; Ye, Zhangqun (2013-08-01). "saRNA guided iNOS up-regulation improves erectile function of diabetic rats". The Journal of Urology. 190 (2): 790–798. doi:10.1016/j.juro.2013.03.043. ISSN   1527-3792. PMID   23523927.
  13. ↑ "First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-06-12.
  14. ↑ Sarkar, Debashis; Plummer, Ruth; Meyer, Tim; Sodergren, Mikael H.; and 32 further, co-authors (2020). "MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial". Clinical Cancer Research. 26 (15): 3936–3946. doi: 10.1158/1078-0432.CCR-20-0414 . hdl: 10044/1/81948 . PMID   32357963 . Retrieved 29 January 2021.{{cite journal}}: CS1 maint: numeric names: authors list (link)

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