Biology:saRNA

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Short description: Type of RNA

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

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-kb 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 (https://bioinfo.imtech.res.in/manojk/sarna/) and published.[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. doi:10.1073/pnas.0607015103. ISSN 0027-8424. PMID 17085592. Bibcode: 2006PNAS..10317337L. 
  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. 
  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. doi:10.1371/journal.pone.0008848. ISSN 1932-6203. PMID 20107511. Bibcode: 2010PLoSO...5.8848H. 
  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. 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. PMID 23344177. 
  6. ↑ Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Manoharan, Muthiah; Corey, David R. et al. (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. 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. 
  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 et al. (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. 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. doi:10.1371/journal.pone.0153117. ISSN 1932-6203. PMID 27050434. Bibcode: 2016PLoSO..1153117H. 
  11. ↑ Yoon, Sorah; Huang, Kai-Wen; Reebye, Vikash; Mintz, Paul; Tien, Yu-Wen; Lai, Hong-Shiee; Sætrom, Pål; Reccia, Isabella et al. (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. PMID 26983359. 
  12. ↑ Wang, Tao; Li, Mingchao; Yuan, Huixin; Zhan, Yin; Xu, Hua; Wang, Shaogang; Yang, Weiming; Liu, Jihong et al. (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". https://clinicaltrials.gov/ct2/show/NCT02716012. 
  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. PMID 32357963. https://clincancerres.aacrjournals.org/content/26/15/3936. Retrieved 29 January 2021. 

Further reading

  • Morris KV (2008). RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press ISBN:978-1-904455-25-7
  • Tost J (2008). Epigenetics. Caister Academic Press ISBN:978-1-904455-23-3

External links



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