Editing Small interfering RNA (section)

== RNA activation ==  

{{Main|RNA activation}}  

In addition to their role in RNAi, siRNAs can also activate gene expression, a phenomenon termed "[[RNA activation]]" or RNAa.  This was first observed when synthetic siRNAs, termed "[[small activating RNA]]" (saRNA), targeting gene promoters were found to induce potent transcriptional activation of target genes.<ref name="Li2006_PNAS">{{cite journal | vauthors = Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S, Enokida H, Dahiya R | title = Small dsRNAs induce transcriptional activation in human cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 46 | pages = 17337–42 | date = November 2006 | pmid = 17085592 | pmc = 1859931 | doi = 10.1073/pnas.0607015103 | doi-access = free | bibcode = 2006PNAS..10317337L }}</ref>  RNAa has been demonstrated to be a conserved mechanism, observed across species from insects, ''C. elegans'', and plants, to mammals (including humans).<ref name="Huang2010">{{cite journal | vauthors = Huang V, Qin Y, Wang J, Wang X, Place RF, Lin G, Lue TF, Li LC | title = RNAa is conserved in mammalian cells | journal = PLOS ONE | volume = 5 | issue = 1 | pages = e8848 | date = January 2010 | pmid = 20107511 | pmc = 2809750 | doi = 10.1371/journal.pone.0008848 | bibcode = 2010PLoSO...5.8848H | editor1-last = Jin | editor1-first = Dong-Yan | doi-access = free }}</ref><ref name="DeHayr2020">{{cite journal | vauthors = De Hayr L, Asad S, Hussain M, and Asgari S | title = RNA activation in insects: The targeted activation of endogenous and exogenous genes | journal = Insect Biochem Mol Biol | volume = 119 | pages = 103325 | date = 2020 | pmid = 31981686 | doi = 10.1016/j.ibmb.2020.103325}}</ref><ref name="Claycomb2009">{{cite journal | vauthors = Claycomb JM, Batista PJ, Pang KM, et al. | title = The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation | journal = Cell | volume = 139 | issue = 1 | pages = 123–134 | date = 2009 | pmid = 19804756 | pmc = 2762760 | doi = 10.1016/j.cell.2009.09.014}}</ref><ref name="Shibuya2009">{{cite journal | vauthors = Shibuya K, Fukushima S, and Takatsuji H | title = RNA-directed DNA methylation induces transcriptional activation in plants | journal = Proc Natl Acad Sci U S A | volume = 106 | issue = 5 | pages = 1660–1665 | date = 2009 | pmid = 19164525 | pmc = 2629447 | doi = 10.1073/pnas.0809294106 | bibcode = 2009PNAS..106.1660S | doi-access = free }}</ref>  

The mechanism of RNAa involves the targeting of promoter regions by saRNAs, leading to the recruitment of transcriptional machinery and epigenetic changes that promote gene expression.  This process often involves the RNA-induced transcriptional activation (RITA) complex, which includes [[Argonaute]] proteins (particularly Ago2), RNA helicase A (RHA), and CTR9.<ref name="Portnoy2016">{{cite journal | vauthors = Portnoy V, Lin SH, Li KH, Burlingame A, Hu ZH, Li H, Li LC | title = saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription | journal = Cell Research | volume = 26 | issue = 3 | pages = 320–35 | date = March 2016 | pmid = 26902284 | pmc = 4783471 | doi = 10.1038/cr.2016.22 }}</ref><ref name="Voutila2017">{{cite journal | vauthors = Voutila J, Reebye V, Roberts TC, Protopapa P, Andrikakou P, Blakey DC, Habib R, Huber H, Saetrom P, Rossi JJ, Habib NA | title = Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer | journal = Molecular Therapy | volume = 25 | issue = 12 | pages = 2705– 2714 | date = December 2017 | pmid = 28882451 | pmc = 5768526 | doi = 10.1016/j.ymthe.2017.07.018 }}</ref> Endogenous miRNAs can also mediate RNAa, expanding the regulatory roles of these small RNAs beyond gene silencing.  

Several saRNA-based therapeutics are currently in clinical development.  MTL-CEBPA, developed by MiNA Therapeutics, targets the ''CEBPA'' gene and is in Phase II trials for liver cancer.<ref name="Sarker2020">{{cite journal | vauthors = Sarker D, Plummer R, Meyer T, et al. | title = MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-alpha, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial | journal = Clin Cancer Res | volume = 26 | issue = 15 | pages = 3936–3946 | date = 2020 | pmid = 32354749 | pmc = 7403143 | doi = 10.1158/1078-0432.CCR-19-3706}}</ref> RAG-01, developed by Ractigen Therapeutics, targets the ''p21'' gene and is in Phase I trials for non-muscle invasive bladder cancer (NMIBC).<ref name="Ractigen2024">Ractigen (2024.4). Ractigen Therapeutics Announces FDA Approval for RAG-01, a First-in-Class saRNA Therapy for BCG-Unresponsive NMIBC [https://www.ractigen.com/ractigen-therapeutics-announces-fda-approval-for-rag-01-a-first-in-class-sarna-therapy-for-bcg-unresponsive-nmibc/](https://www.ractigen.com/ractigen-therapeutics-announces-fda-approval-for-rag-01-a-first-in-class-sarna-therapy-for-bcg-unresponsive-nmibc/).</ref> These clinical trials represent a significant step towards translating the RNAa phenomenon into novel therapeutic strategies.