From Wikipedia, the free encyclopedia
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
^ 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