Small activating RNA explained

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).

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 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]

Further reading

External links

Notes and 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. 10.1073/pnas.0607015103. 0027-8424. 1859931. 17085592. 2006PNAS..10317337L. free.
  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. 10.1038/nchembio860. 1552-4450. 17259978. 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. 10.1371/journal.pone.0008848. 1932-6203. 2809750. 20107511. 2010PLoSO...5.8848H. free.
  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. 10.14440/jbm.2015.39. 2326-9901. 4379447. 25839046. 14.
  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. 10.1038/mtna.2012.20. 2162-2531. 3437803. 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. 10.1093/nar/gkt777. 1362-4962. 3905862. 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. 10.1016/j.jmb.2018.03.023. 29625201. 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. 10.1158/0008-5472.CAN-12-1871. 1538-7445. 22869584. free.
  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. 10.1002/hep.26669. 1527-3350. 4655108. 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. 10.1371/journal.pone.0153117. 1932-6203. 4822802. 27050434. 2016PLoSO..1153117H. free.
  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. 10.1038/mt.2016.60. 1525-0024. 26983359. 24. 6. 4923325. 1106–16.
  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. 10.1016/j.juro.2013.03.043. 1527-3792. 23523927.
  13. Web site: First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov. clinicaltrials.gov. 2016-06-12.
  14. Sarkar . Debashis . Plummer . Ruth . Meyer . Tim . Sodergren . Mikael H. . and 32 further . co-authors . 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 . 2020 . 26 . 15 . 3936–3946 . 10.1158/1078-0432.CCR-20-0414 . 32357963 . 29 January 2021. free . 10044/1/81948 . free .

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