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
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "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.
-
^ 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)
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
- Small RNAs Reveal an Activating Side. Science News of the Week
- How to get your genes switched on. New Scientist 16 November 2006
- Bladder cancer: Intravesical RNA activation—a new treatment concept. Nature Review Urology October 2012
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
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "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.
-
^ 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)
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
- Small RNAs Reveal an Activating Side. Science News of the Week
- How to get your genes switched on. New Scientist 16 November 2006
- Bladder cancer: Intravesical RNA activation—a new treatment concept. Nature Review Urology October 2012