SaRNA

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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).

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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]

Related Research Articles

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Regulator gene</span> Gene involved in controlling expression of other genes

In genetics, a regulator gene, regulator, or regulatory gene is a gene involved in controlling the expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often at the five prime end (5') to the start site of transcription of the gene they regulate. In addition, these sequences can also be found at the three prime end (3') to the transcription start site. In both cases, whether the regulatory sequence occurs before (5') or after (3') the gene it regulates, the sequence is often many kilobases away from the transcription start site. A regulator gene may encode a protein, or it may work at the level of RNA, as in the case of genes encoding microRNAs. An example of a regulator gene is a gene that codes for a repressor protein that inhibits the activity of an operator.

<span class="mw-page-title-main">Transcription factor Sp1</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.

Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN). c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.

RNA activation (RNAa) is a small RNA-guided and Argonaute (Ago)-dependent gene regulation phenomenon in which promoter-targeted short double-stranded RNAs (dsRNAs) induce target gene expression at the transcriptional/epigenetic level. RNAa was first reported in a 2006 PNAS paper by Li et al. who also coined the term "RNAa" as a contrast to RNA interference (RNAi) to describe such gene activation phenomenon. dsRNAs that trigger RNAa have been termed small activating RNA (saRNA). Since the initial discovery of RNAa in human cells, many other groups have made similar observations in different mammalian species including human, non-human primates, rat and mice, plant and C. elegans, suggesting that RNAa is an evolutionarily conserved mechanism of gene regulation.

<span class="mw-page-title-main">Corepressor</span> Molecule that represses the expression of genes

In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, but instead indirectly regulates gene expression by binding to repressors.

<span class="mw-page-title-main">Liver X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

<span class="mw-page-title-main">MTA2</span> Protein-coding gene in the species Homo sapiens

Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2 gene.

mIRN21 Non-coding RNA in the species Homo sapiens

microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.

<span class="mw-page-title-main">HBx</span>

HBx is a hepatitis B viral protein. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. It interacts with DDB1 redirecting the ubiquitin ligase activity of the CUL4-DDB1 E3 complexes, which are intimately involved in the intracellular regulation of DNA replication and repair, transcription and signal transduction.

mir-127

mir-127 microRNA is a short non-coding RNA molecule with interesting overlapping gene structure. miR-127 functions to regulate the expression levels of genes involved in lung development, placental formation and apoptosis. Aberrant expression of miR-127 has been linked to different cancers.

<span class="mw-page-title-main">KLF15</span> Protein-coding gene in the species Homo sapiens

Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.

<span class="mw-page-title-main">HOXA11-AS1</span> Long non-coding RNA from the antisense strand in the homeobox A (HOXA gene).

HOXA11-AS lncRNA is a long non-coding RNA from the antisense strand in the homeobox A. The HOX gene contains four clusters. The sense strand of the HOXA gene codes for proteins. Alternative names for HOXA11-AS lncRNA are: HOXA-AS5, HOXA11S, HOXA11-AS1, HOXA11AS, or NCRNA00076. This gene is 3,885 nucleotides long and resides at chromosome 7 (7p15.2) and is transcribed from an independent gene promoter. Being a lncRNA, it is longer than 200 nucleotides in length, in contrast to regular non-coding RNAs.

In molecular biology mir-885 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

<span class="mw-page-title-main">Zinc finger protein 226</span> Protein found in humans

Zinc finger protein 226 is a protein that in humans is encoded by the ZNF226 gene.

DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

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. Bibcode:2006PNAS..10317337L. doi: 10.1073/pnas.0607015103 . ISSN   0027-8424. PMC   1859931 . PMID   17085592.
  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. S2CID   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. Bibcode:2010PLoSO...5.8848H. doi: 10.1371/journal.pone.0008848 . ISSN   1932-6203. PMC   2809750 . PMID   20107511.
  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 (inactive 2024-02-22). ISSN   2326-9901. PMC   4379447 . PMID   25839046.{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
  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. PMC   3437803 . PMID   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. doi:10.1093/nar/gkt777. ISSN   1362-4962. PMC   3905862 . 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. S2CID   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. 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; 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.
  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. Bibcode:2016PLoSO..1153117H. doi: 10.1371/journal.pone.0153117 . ISSN   1932-6203. PMC   4822802 . PMID   27050434.
  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. 24 (6): 1106–16. doi:10.1038/mt.2016.60. ISSN   1525-0024. PMC   4923325 . PMID   26983359.
  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. 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". clinicaltrials.gov. Retrieved 2016-06-12.
  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 . hdl: 10044/1/81948 . PMID   32357963 . Retrieved 29 January 2021.{{cite journal}}: CS1 maint: numeric names: authors list (link)

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