RNA activation

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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.[1] who also coined the term "RNAa" as a contrast to RNA interference (RNAi)[1] to describe such gene activation phenomenon. Soon after, several groups made similar observation in different mammalian species including human, non-human primates, rat and mice,[2][3][4][5] suggesting that RNAa is a general gene regulation mechanism conserved at least in mammals. In these studies, upregulation of gene expression is achieved by targeting selected promoter regions using either synthetic 21-nucleotide dsRNAs or vector expressed small hairpin RNAs (shRNAs). Such promoter targeted dsRNAs have been termed antigene RNA (agRNAs)[5] or small activating RNA (saRNA).[1][6]

Similar gene activation mechanisms mediated by the Ago-small RNA pathway have also been observed in plants [7] and C. elegans.[8][9]

Mechanism of RNAa[edit]

The molecular mechanism of RNAa is not fully understood. Similar to RNAi, it has been shown that mammalian RNAa requires members of the Ago clade of Argonaute proteins, particularly Ago2,[1][10] but possesses kinetics distinct from RNAi.[11] In contrast to RNAi, promoter-targeted agRNAs induce prolonged activation of gene expression associated with epigenetic changes.[12] It is currently suggested that saRNAs are first loaded and processed by an Ago protein to form an Ago-RNA complex which is then guided by the RNA to its promoter target. The target can be a non-coding transcript overlapping the promoter[5][10] or the chromosomal DNA.[12][13] The RNA-loaded Ago then recruits other proteins such as RHA, also known as nuclear DNA helicase II, and CTR9 to form an RNA-induced transcriptional activation (RITA) complex. RITA can directly interacts with RNAP II to stimulate transcription initiation and productive transcription elongation which is related to increased ubiquitination of H2B.[14][15]. In C. elegans, Turner et al.[9] recently identified a conserved miRNA (lin-4 microRNA) which acts endogenously to activate gene expression [16].

Endogenous RNAa[edit]

In 2008, Place et al. identified targets for miRNA miR-373 on the promoters of several human genes and found that introduction of miR-373 mimics into human cells induced the expression of its predicted target genes. This study provided the first example that RNAa could be mediated by naturally occurring non-coding RNA (ncRNA).[17] In 2011, Huang et al. further demonstrated in mouse cells that endogenous RNAa mediated by miRNAs functions in a physiological context and is possibly exploited by cancer cells to gain a growth advantage.[18] Since then, a number of miRNAs have been shown to upregulate gene expression by targeting gene promoters [19][20][21][22] or enhancers.[23] A good example is miR-551b-3p which is overexpressed in ovarian cancer due to amplification.[21] miR-551b-3p confers to ovarian cancer cells resistance to apoptosis and a proliferative advantage by targeting the promoter of STAT3 to increase its transcription.[21]

In C. elegans, Argonaute CSR-1 interacts with 22G small RNAs derived from RNA-dependent RNA polymerase and antisense to germline-expressed transcripts to protect these mRNAs from Piwi-piRNA mediated silencing via promoting epigenetic activation.[24][25] In C. elegans hypodermal seam cells, the transcription of lin-4 miRNA is positively regulated by lin-4 itself which binds to a conserved lin-4 complementary element in its promoter, constituting a positive autoregulatory loop.[9]

Applications of RNAa[edit]

RNAa has been used to study gene function in lieu of vector-based gene overexpression.[26] Studies have demonstrated RNAa in vivo and its potential therapeutic applications in treating cancer and non-cancerous diseases.[3][27][28][29][30][31][32]

In June 2016, UK-based MiNA Therapeutics announced the initiation of a phase I trial of the first-ever saRNA drug MTL-CEBPA in patients with liver cancer, in an attempt to activate CEBPA gene.[33][34]

References[edit]

  1. ^ a b c d Li, Long-Cheng; Okino, Steven T.; Zhao, Hong; Pookot, Deepa; Place, Robert F.; Urakami, Shinji; Enokida, Hideki; Dahiya, Rajvir (2006). "Small dsRNAs induce transcriptional activation in human cells". Proceedings of the National Academy of Sciences. 103 (46): 17337–42. doi:10.1073/pnas.0607015103. PMC 1859931Freely accessible. PMID 17085592. [non-primary source needed]
  2. ^ Janowski, Bethany A; Younger, Scott T; Hardy, Daniel B; Ram, Rosalyn; Huffman, Kenneth E; Corey, David R (2007). "Activating gene expression in mammalian cells with promoter-targeted duplex RNAs". Nature Chemical Biology. 3 (3): 166–73. doi:10.1038/nchembio860. PMID 17259978. 
  3. ^ a b Turunen, Mikko P.; Lehtola, Tiia; Heinonen, Suvi E.; Assefa, Genet S.; Korpisalo, Petra; Girnary, Roseanne; Glass, Christopher K.; Väisänen, Sami; Ylä-Herttuala, Seppo (2009). "Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism: A Novel Example of Epigenetherapy". Circulation Research. 105 (6): 604–9. doi:10.1161/CIRCRESAHA.109.200774. PMID 19696410. 
  4. ^ Huang, Vera; Qin, Yi; Wang, Ji; Wang, Xiaoling; Place, Robert F.; Lin, Guiting; Lue, Tom F.; Li, Long-Cheng (2010). Jin, Dong-Yan, ed. "RNAa is Conserved in Mammalian Cells". PLoS ONE. 5 (1): e8848. doi:10.1371/journal.pone.0008848. PMC 2809750Freely accessible. PMID 20107511. 
  5. ^ a b c Matsui, Masayuki; Sakurai, Fuminori; Elbashir, Sayda; Foster, Donald J.; Manoharan, Muthiah; Corey, David R. (2010). "Activation of LDL Receptor Expression by Small RNAs Complementary to a Noncoding Transcript that Overlaps the LDLR Promoter". Chemistry & Biology. 17 (12): 1344–55. doi:10.1016/j.chembiol.2010.10.009. PMC 3071588Freely accessible. PMID 21168770. 
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Further reading[edit]

External links[edit]