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Added description of the RITA complex in the Mechanism section, added citations to the endogenous RNAa sections.
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'''RNA activation''' (RNAa) is a small RNA-guided and Argonaute-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.''<ref name="li_pnas">{{cite journal |pages=17337–42 |doi=10.1073/pnas.0607015103 |title=Small dsRNAs induce transcriptional activation in human cells |year=2006 |last1=Li |first1=Long-Cheng |last2=Okino |first2=Steven T. |last3=Zhao |first3=Hong |last4=Pookot |first4=Deepa |last5=Place |first5=Robert F. |last6=Urakami |first6=Shinji |last7=Enokida |first7=Hideki |last8=Dahiya |first8=Rajvir |journal=Proceedings of the National Academy of Sciences |volume=103 |issue=46 |pmid=17085592 |pmc=1859931}}{{psc|date=December 2011}}</ref> who also coined the term "RNAa" as a contrast to [[RNA interference]] ([[RNAi]])<ref name="li_pnas" /> 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,<ref name="ncb">{{cite journal |pages=166–73 |doi=10.1038/nchembio860 |title=Activating gene expression in mammalian cells with promoter-targeted duplex RNAs |year=2007 |last1=Janowski |first1=Bethany A |last2=Younger |first2=Scott T |last3=Hardy |first3=Daniel B |last4=Ram |first4=Rosalyn |last5=Huffman |first5=Kenneth E |last6=Corey |first6=David R |journal=Nature Chemical Biology |volume=3 |issue=3 |pmid=17259978}}</ref><ref name="circres">{{cite journal |pages=604–9 |doi=10.1161/CIRCRESAHA.109.200774 |title=Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism: A Novel Example of Epigenetherapy |year=2009 |last1=Turunen |first1=Mikko P. |last2=Lehtola |first2=Tiia |last3=Heinonen |first3=Suvi E. |last4=Assefa |first4=Genet S. |last5=Korpisalo |first5=Petra |last6=Girnary |first6=Roseanne |last7=Glass |first7=Christopher K. |last8=Väisänen |first8=Sami |last9=Ylä-Herttuala |first9=Seppo |journal=Circulation Research |volume=105 |issue=6 |pmid=19696410 }}</ref><ref>{{cite journal | doi=10.1371/journal.pone.0008848 | title=RNAa is Conserved in Mammalian Cells | year=2010 | editor1-last=Jin | editor1-first=Dong-Yan | last1=Huang | first1=Vera | last2=Qin | first2=Yi | last3=Wang | first3=Ji | last4=Wang | first4=Xiaoling | last5=Place | first5=Robert F. | last6=Lin | first6=Guiting | last7=Lue | first7=Tom F. | last8=Li | first8=Long-Cheng | journal=PLoS ONE | volume=5 | pages=e8848 | pmid=20107511 | issue=1 | pmc=2809750}}</ref><ref name="coreychembio">{{cite journal |pages=1344–55 |doi=10.1016/j.chembiol.2010.10.009 |pmc=3071588 |title=Activation of LDL Receptor Expression by Small RNAs Complementary to a Noncoding Transcript that Overlaps the LDLR Promoter |year=2010 |last1=Matsui |first1=Masayuki |last2=Sakurai |first2=Fuminori |last3=Elbashir |first3=Sayda |last4=Foster |first4=Donald J. |last5=Manoharan |first5=Muthiah |last6=Corey |first6=David R. |journal=Chemistry & Biology |volume=17 |issue=12 |pmid=21168770}}</ref> 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)<ref name="coreychembio"/> or small activating RNA ([[saRNA]]).<ref name="li_pnas"/><ref name=VoutilaMTNA>{{cite journal|last=Voutila|first=J|author2=Sætrom, P |author3=Mintz, P |author4=Sun, G |author5=Alluin, J |author6=Rossi, JJ |author7=Habib, NA |author8= Kasahara, N |title=Gene Expression Profile Changes After Short-activating RNA-mediated Induction of Endogenous Pluripotency Factors in Human Mesenchymal Stem Cells.|journal=Molecular Therapy: Nucleic Acids|date=Aug 7, 2012|volume=1|pages=e35|pmid=23344177|doi=10.1038/mtna.2012.20 |issue=8 |pmc=3437803}}</ref>
'''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.''<ref name="li_pnas">{{cite journal |pages=17337–42 |doi=10.1073/pnas.0607015103 |title=Small dsRNAs induce transcriptional activation in human cells |year=2006 |last1=Li |first1=Long-Cheng |last2=Okino |first2=Steven T. |last3=Zhao |first3=Hong |last4=Pookot |first4=Deepa |last5=Place |first5=Robert F. |last6=Urakami |first6=Shinji |last7=Enokida |first7=Hideki |last8=Dahiya |first8=Rajvir |journal=Proceedings of the National Academy of Sciences |volume=103 |issue=46 |pmid=17085592 |pmc=1859931}}{{psc|date=December 2011}}</ref> who also coined the term "RNAa" as a contrast to [[RNA interference]] ([[RNAi]])<ref name="li_pnas" /> 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,<ref name="ncb">{{cite journal |pages=166–73 |doi=10.1038/nchembio860 |title=Activating gene expression in mammalian cells with promoter-targeted duplex RNAs |year=2007 |last1=Janowski |first1=Bethany A |last2=Younger |first2=Scott T |last3=Hardy |first3=Daniel B |last4=Ram |first4=Rosalyn |last5=Huffman |first5=Kenneth E |last6=Corey |first6=David R |journal=Nature Chemical Biology |volume=3 |issue=3 |pmid=17259978}}</ref><ref name="circres">{{cite journal |pages=604–9 |doi=10.1161/CIRCRESAHA.109.200774 |title=Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism: A Novel Example of Epigenetherapy |year=2009 |last1=Turunen |first1=Mikko P. |last2=Lehtola |first2=Tiia |last3=Heinonen |first3=Suvi E. |last4=Assefa |first4=Genet S. |last5=Korpisalo |first5=Petra |last6=Girnary |first6=Roseanne |last7=Glass |first7=Christopher K. |last8=Väisänen |first8=Sami |last9=Ylä-Herttuala |first9=Seppo |journal=Circulation Research |volume=105 |issue=6 |pmid=19696410 }}</ref><ref>{{cite journal | doi=10.1371/journal.pone.0008848 | title=RNAa is Conserved in Mammalian Cells | year=2010 | editor1-last=Jin | editor1-first=Dong-Yan | last1=Huang | first1=Vera | last2=Qin | first2=Yi | last3=Wang | first3=Ji | last4=Wang | first4=Xiaoling | last5=Place | first5=Robert F. | last6=Lin | first6=Guiting | last7=Lue | first7=Tom F. | last8=Li | first8=Long-Cheng | journal=PLoS ONE | volume=5 | pages=e8848 | pmid=20107511 | issue=1 | pmc=2809750}}</ref><ref name="coreychembio">{{cite journal |pages=1344–55 |doi=10.1016/j.chembiol.2010.10.009 |pmc=3071588 |title=Activation of LDL Receptor Expression by Small RNAs Complementary to a Noncoding Transcript that Overlaps the LDLR Promoter |year=2010 |last1=Matsui |first1=Masayuki |last2=Sakurai |first2=Fuminori |last3=Elbashir |first3=Sayda |last4=Foster |first4=Donald J. |last5=Manoharan |first5=Muthiah |last6=Corey |first6=David R. |journal=Chemistry & Biology |volume=17 |issue=12 |pmid=21168770}}</ref> 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)<ref name="coreychembio"/> or [[SaRNA|small activating RNA]] ([[saRNA]]).<ref name="li_pnas"/><ref name=VoutilaMTNA>{{cite journal|last=Voutila|first=J|author2=Sætrom, P |author3=Mintz, P |author4=Sun, G |author5=Alluin, J |author6=Rossi, JJ |author7=Habib, NA |author8= Kasahara, N |title=Gene Expression Profile Changes After Short-activating RNA-mediated Induction of Endogenous Pluripotency Factors in Human Mesenchymal Stem Cells.|journal=Molecular Therapy: Nucleic Acids|date=Aug 7, 2012|volume=1|pages=e35|pmid=23344177|doi=10.1038/mtna.2012.20 |issue=8 |pmc=3437803}}</ref>


Similar gene activation mechanisms mediated by Argonaute-small RNAs have also been observed in plants <ref>{{cite journal |pages=1660–5 |doi=10.1073/pnas.0809294106 |pmc=2629447 |title=RNA-directed DNA methylation induces transcriptional activation in plants |year=2009 |last1=Shibuya |first1=Kenichi |last2=Fukushima |first2=Setsuko |last3=Takatsuji |first3=Hiroshi |journal=Proceedings of the National Academy of Sciences |volume=106 |issue=5 |pmid=19164525}}</ref> and C. elegans.<ref>{{Cite journal|last=Seth|first=Meetu|last2=Shirayama|first2=Masaki|last3=Gu|first3=Weifeng|last4=Ishidate|first4=Takao|last5=Conte|first5=Darryl|last6=Mello|first6=Craig C.|date=2013-12-23|title=The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression|journal=Developmental Cell|volume=27|issue=6|pages=656–663|doi=10.1016/j.devcel.2013.11.014|issn=1878-1551|pmc=3954781|pmid=24360782}}</ref><ref name="turner_cellcycle">{{cite journal|last=Turner|first=MJ|author2=Jiao, AL |author3=Slack, FJ |title=Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans.|journal=Cell cycle (Georgetown, Tex.)|date=Jan 7, 2014|volume=13|issue=5|pmid=24398561|doi=10.4161/cc.27679|pages=772–81}}</ref>
Similar gene activation mechanisms mediated by the Ago-small RNA pathway have also been observed in plants <ref>{{cite journal |pages=1660–5 |doi=10.1073/pnas.0809294106 |pmc=2629447 |title=RNA-directed DNA methylation induces transcriptional activation in plants |year=2009 |last1=Shibuya |first1=Kenichi |last2=Fukushima |first2=Setsuko |last3=Takatsuji |first3=Hiroshi |journal=Proceedings of the National Academy of Sciences |volume=106 |issue=5 |pmid=19164525}}</ref> and C. elegans.<ref>{{Cite journal|last=Seth|first=Meetu|last2=Shirayama|first2=Masaki|last3=Gu|first3=Weifeng|last4=Ishidate|first4=Takao|last5=Conte|first5=Darryl|last6=Mello|first6=Craig C.|date=2013-12-23|title=The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression|journal=Developmental Cell|volume=27|issue=6|pages=656–663|doi=10.1016/j.devcel.2013.11.014|issn=1878-1551|pmc=3954781|pmid=24360782}}</ref><ref name="turner_cellcycle">{{cite journal|last=Turner|first=MJ|author2=Jiao, AL |author3=Slack, FJ |title=Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans.|journal=Cell cycle (Georgetown, Tex.)|date=Jan 7, 2014|volume=13|issue=5|pmid=24398561|doi=10.4161/cc.27679|pages=772–81}}</ref>


==Mechanism of RNAa==
==Mechanism of RNAa==
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,<ref name="li_pnas" /><ref name="coreynar">{{cite journal |pages=7736–48 |doi=10.1093/nar/gkq648 |pmc=2995069 |title=Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter |year=2010 |last1=Chu |first1=Yongjun |last2=Yue |first2=Xuan |last3=Younger |first3=Scott T. |last4=Janowski |first4=Bethany A. |last5=Corey |first5=David R. |journal=Nucleic Acids Research |volume=38 |issue=21 |pmid=20675357}}</ref> but possesses kinetics distinct from RNAi.<ref name=LiLC>{{cite book |chapterurl=https://books.google.com/books?id=r67Lrf9r9XEC&pg=PA189 |last=Li |first=Long-Cheng |year=2008 |chapter=Small RNA-mediated gene activation |editor1-first=Kevin V |editor1-last=Morris |title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity |publisher=Caister Academic Press |isbn=978-1-904455-25-7 |pages=189–99}}</ref> In contrast to RNAi, promoter-targeted agRNAs induce prolonged activation of gene expression associated with epigenetic changes.<ref name="WIREsRNA">{{cite journal |pages=748–60 |doi=10.1002/wrna.90 |title=Small RNA and transcriptional upregulation |year=2011 |last1=Portnoy |first1=Victoria |last2=Huang |first2=Vera |last3=Place |first3=Robert F. |last4=Li |first4=Long-Cheng |journal=Wiley Interdisciplinary Reviews: RNA |volume=2 |issue=5 |pmid=21823233 |pmc=3154074}}</ref> 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<ref name="coreychembio"/><ref name="coreynar"/> or the chromosomal DNA.<ref name="WIREsRNA" /> Ago then recruits histone modifying enzymes such as histone methyltransferase to the promoter to activate transcription by causing permissive epigenetic changes.<ref>{{Cite journal|last = Portnoy|first = Victoria|last2 = Lin|first2 = Szu Hua Sharon|last3 = Li|first3 = Kathy H.|last4 = Burlingame|first4 = Alma|last5 = Hu|first5 = Zheng-Hui|last6 = Li|first6 = Hao|last7 = Li|first7 = Long-Cheng|date = 2016-03-01|title = saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription|journal = Cell Research|volume = 26|issue = 3|pages = 320–335|doi = 10.1038/cr.2016.22|issn = 1748-7838|pmc = 4783471|pmid = 26902284}}</ref>
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,<ref name="li_pnas" /><ref name="coreynar">{{cite journal |pages=7736–48 |doi=10.1093/nar/gkq648 |pmc=2995069 |title=Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter |year=2010 |last1=Chu |first1=Yongjun |last2=Yue |first2=Xuan |last3=Younger |first3=Scott T. |last4=Janowski |first4=Bethany A. |last5=Corey |first5=David R. |journal=Nucleic Acids Research |volume=38 |issue=21 |pmid=20675357}}</ref> but possesses kinetics distinct from RNAi.<ref name=LiLC>{{cite book |chapterurl=https://books.google.com/books?id=r67Lrf9r9XEC&pg=PA189 |last=Li |first=Long-Cheng |year=2008 |chapter=Small RNA-mediated gene activation |editor1-first=Kevin V |editor1-last=Morris |title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity |publisher=Caister Academic Press |isbn=978-1-904455-25-7 |pages=189–99}}</ref> In contrast to RNAi, promoter-targeted agRNAs induce prolonged activation of gene expression associated with epigenetic changes.<ref name="WIREsRNA">{{cite journal |pages=748–60 |doi=10.1002/wrna.90 |title=Small RNA and transcriptional upregulation |year=2011 |last1=Portnoy |first1=Victoria |last2=Huang |first2=Vera |last3=Place |first3=Robert F. |last4=Li |first4=Long-Cheng |journal=Wiley Interdisciplinary Reviews: RNA |volume=2 |issue=5 |pmid=21823233 |pmc=3154074}}</ref> 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<ref name="coreychembio"/><ref name="coreynar"/> or the chromosomal DNA.<ref name="WIREsRNA" /><ref>{{Cite journal|last=Meng|first=Xing|last2=Jiang|first2=Qian|last3=Chang|first3=Nannan|last4=Wang|first4=Xiaoxia|last5=Liu|first5=Chujun|last6=Xiong|first6=Jingwei|last7=Cao|first7=Huiqing|last8=Liang|first8=Zicai|date=2016-03-18|title=Small activating RNA binds to the genomic target site in a seed-region-dependent manner|url=https://www.ncbi.nlm.nih.gov/pubmed/26873922|journal=Nucleic Acids Research|volume=44|issue=5|pages=2274–2282|doi=10.1093/nar/gkw076|issn=1362-4962|pmc=PMC4797303|pmid=26873922}}</ref> The RNA-loaded Ago then recruits other proteins such as [[RNA Helicase A|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.<ref>{{Cite journal|last = Portnoy|first = Victoria|last2 = Lin|first2 = Szu Hua Sharon|last3 = Li|first3 = Kathy H.|last4 = Burlingame|first4 = Alma|last5 = Hu|first5 = Zheng-Hui|last6 = Li|first6 = Hao|last7 = Li|first7 = Long-Cheng|date = 2016-03-01|title = saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription|journal = Cell Research|volume = 26|issue = 3|pages = 320–335|doi = 10.1038/cr.2016.22|issn = 1748-7838|pmc = 4783471|pmid = 26902284}}</ref><ref>{{Cite journal|last=Voutila|first=Jon|last2=Reebye|first2=Vikash|last3=Roberts|first3=Thomas C.|last4=Protopapa|first4=Pantelitsa|last5=Andrikakou|first5=Pinelopi|last6=Blakey|first6=David C.|last7=Habib|first7=Robert|last8=Huber|first8=Hans|last9=Saetrom|first9=Pal|date=2017-08-04|title=Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer|url=https://www.ncbi.nlm.nih.gov/pubmed/28882451|journal=Molecular Therapy: The Journal of the American Society of Gene Therapy|doi=10.1016/j.ymthe.2017.07.018|issn=1525-0024|pmid=28882451}}</ref>


==Endogenous RNAa==
==Endogenous RNAa==
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]]).<ref>{{cite journal |pages=1608–13 |doi=10.1073/pnas.0707594105 |pmc=2234192 |title=MicroRNA-373 induces expression of genes with complementary promoter sequences |year=2008 |last1=Place |first1=Robert F. |last2=Li |first2=Long-Cheng |last3=Pookot |first3=Deepa |last4=Noonan |first4=Emily J. |last5=Dahiya |first5=Rajvir |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=5 |pmid=18227514}}{{psc|date=December 2011}}</ref> 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.<ref>{{cite journal |doi=10.1093/nar/gkr934 |title=Upregulation of Cyclin B1 by miRNA and its implications in cancer |year=2011 |last1=Huang |first1=Vera |last2=Place |first2=Robert F. |last3=Portnoy |first3=Victoria |last4=Wang |first4=Ji |last5=Qi |first5=Zhongxia |last6=Jia |first6=Zhejun |last7=Yu |first7=Angela |last8=Shuman |first8=Marc |last9=Yu |first9=Jingwei |last10=Li |first10=L.-C. |journal=Nucleic Acids Research |pmid=22053081 |pmc=3287204 |volume=40 |issue=4 |pages=1695–707|display-authors=8 }}{{psc|date=December 2011}}</ref>
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]]).<ref>{{cite journal |pages=1608–13 |doi=10.1073/pnas.0707594105 |pmc=2234192 |title=MicroRNA-373 induces expression of genes with complementary promoter sequences |year=2008 |last1=Place |first1=Robert F. |last2=Li |first2=Long-Cheng |last3=Pookot |first3=Deepa |last4=Noonan |first4=Emily J. |last5=Dahiya |first5=Rajvir |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=5 |pmid=18227514}}{{psc|date=December 2011}}</ref> 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.<ref>{{cite journal |doi=10.1093/nar/gkr934 |title=Upregulation of Cyclin B1 by miRNA and its implications in cancer |year=2011 |last1=Huang |first1=Vera |last2=Place |first2=Robert F. |last3=Portnoy |first3=Victoria |last4=Wang |first4=Ji |last5=Qi |first5=Zhongxia |last6=Jia |first6=Zhejun |last7=Yu |first7=Angela |last8=Shuman |first8=Marc |last9=Yu |first9=Jingwei |last10=Li |first10=L.-C. |journal=Nucleic Acids Research |pmid=22053081 |pmc=3287204 |volume=40 |issue=4 |pages=1695–707|display-authors=8 }}{{psc|date=December 2011}}</ref> Since then, a number of miRNAs have been shown to upregulate gene expression by targeting gene promoters <ref>{{Cite journal|last=Matsui|first=Masayuki|last2=Chu|first2=Yongjun|last3=Zhang|first3=Huiying|last4=Gagnon|first4=Keith T.|last5=Shaikh|first5=Sarfraz|last6=Kuchimanchi|first6=Satya|last7=Manoharan|first7=Muthiah|last8=Corey|first8=David R.|last9=Janowski|first9=Bethany A.|date=December 2013|title=Promoter RNA links transcriptional regulation of inflammatory pathway genes|url=https://www.ncbi.nlm.nih.gov/pubmed/23999091|journal=Nucleic Acids Research|volume=41|issue=22|pages=10086–10109|doi=10.1093/nar/gkt777|issn=1362-4962|pmc=PMC3905862|pmid=23999091}}</ref><ref>{{Cite journal|last=Dharap|first=Ashutosh|last2=Pokrzywa|first2=Courtney|last3=Murali|first3=Shruthi|last4=Pandi|first4=Gopal|last5=Vemuganti|first5=Raghu|date=2013|title=MicroRNA miR-324-3p induces promoter-mediated expression of RelA gene|url=https://www.ncbi.nlm.nih.gov/pubmed/24265774|journal=PloS One|volume=8|issue=11|pages=e79467|doi=10.1371/journal.pone.0079467|issn=1932-6203|pmc=PMC3827167|pmid=24265774}}</ref><ref name=":0">{{Cite journal|last=Chaluvally-Raghavan|first=Pradeep|last2=Jeong|first2=Kang Jin|last3=Pradeep|first3=Sunila|last4=Silva|first4=Andreia Machado|last5=Yu|first5=Shuangxing|last6=Liu|first6=Wenbin|last7=Moss|first7=Tyler|last8=Rodriguez-Aguayo|first8=Cristian|last9=Zhang|first9=Dong|date=2016-05-17|title=Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer|url=https://www.ncbi.nlm.nih.gov/pubmed/27160903|journal=Cell Reports|volume=15|issue=7|pages=1493–1504|doi=10.1016/j.celrep.2016.04.034|issn=2211-1247|pmc=PMC4914391|pmid=27160903}}</ref><ref>{{Cite journal|last=Li|first=Senmao|last2=Wang|first2=Chenghe|last3=Yu|first3=Xiao|last4=Wu|first4=Huanlei|last5=Hu|first5=Jia|last6=Wang|first6=Shaogang|last7=Ye|first7=Zhangqun|date=January 2017|title=miR-3619-5p inhibits prostate cancer cell growth by activating CDKN1A expression|url=https://www.ncbi.nlm.nih.gov/pubmed/27878260|journal=Oncology Reports|volume=37|issue=1|pages=241–248|doi=10.3892/or.2016.5250|issn=1791-2431|pmid=27878260}}</ref> or enhancers.<ref>{{Cite journal|last=Xiao|first=Min|last2=Li|first2=Jin|last3=Li|first3=Wei|last4=Wang|first4=Yu|last5=Wu|first5=Feizhen|last6=Xi|first6=Yanping|last7=Zhang|first7=Lan|last8=Ding|first8=Chao|last9=Luo|first9=Huaibing|date=2016-02-06|title=MicroRNAs activate gene transcription epigenetically as an enhancer trigger|url=https://www.ncbi.nlm.nih.gov/pubmed/26853707|journal=RNA biology|pages=1–9|doi=10.1080/15476286.2015.1112487|issn=1555-8584|pmid=26853707}}</ref> A good example is miR-551b-3p which is overexpressed in ovarian cancer due to amplification.<ref name=":0" /> 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.<ref name=":0" />


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.<ref>{{Cite journal|last=Conine|first=Colin C.|last2=Moresco|first2=James J.|last3=Gu|first3=Weifeng|last4=Shirayama|first4=Masaki|last5=Conte|first5=Darryl|last6=Yates|first6=John R.|last7=Mello|first7=Craig C.|date=2013-12-19|title=Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans|journal=Cell|volume=155|issue=7|pages=1532–1544|doi=10.1016/j.cell.2013.11.032|issn=1097-4172|pmc=3924572|pmid=24360276}}</ref><ref>{{cite journal|last=Wedeles|first=CJ|author2=Wu, MZ |author3=Claycomb, JM |title=Protection of Germline Gene Expression by the C. elegans Argonaute CSR-1.|journal=Developmental Cell|date=Dec 18, 2013|pmid=24360783|doi=10.1016/j.devcel.2013.11.016|volume=27|issue=6|pages=664–71}}</ref> 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.<ref name="turner_cellcycle" />
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.<ref>{{Cite journal|last=Conine|first=Colin C.|last2=Moresco|first2=James J.|last3=Gu|first3=Weifeng|last4=Shirayama|first4=Masaki|last5=Conte|first5=Darryl|last6=Yates|first6=John R.|last7=Mello|first7=Craig C.|date=2013-12-19|title=Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans|journal=Cell|volume=155|issue=7|pages=1532–1544|doi=10.1016/j.cell.2013.11.032|issn=1097-4172|pmc=3924572|pmid=24360276}}</ref><ref>{{cite journal|last=Wedeles|first=CJ|author2=Wu, MZ |author3=Claycomb, JM |title=Protection of Germline Gene Expression by the C. elegans Argonaute CSR-1.|journal=Developmental Cell|date=Dec 18, 2013|pmid=24360783|doi=10.1016/j.devcel.2013.11.016|volume=27|issue=6|pages=664–71}}</ref> In C. elegans hypodermal seam cells, the transcription of [[Lin-4 microRNA precursor|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.<ref name="turner_cellcycle" />


==Applications of RNAa==
==Applications of RNAa==

Revision as of 16:20, 15 September 2017

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

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]

Endogenous RNAa

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).[16] 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.[17] Since then, a number of miRNAs have been shown to upregulate gene expression by targeting gene promoters [18][19][20][21] or enhancers.[22] A good example is miR-551b-3p which is overexpressed in ovarian cancer due to amplification.[20] 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.[20]

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.[23][24] 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

RNAa has been used to study gene function in lieu of vector-based gene overexpression.[25] Studies have demonstrated RNAa in vivo and its potential therapeutic applications in treating cancer and non-cancerous diseases.[3][26][27][28][29][30][31]

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.[32][33]

References

  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 1859931. 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 2809750. PMID 20107511.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  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 3071588. PMID 21168770.
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  13. ^ Meng, Xing; Jiang, Qian; Chang, Nannan; Wang, Xiaoxia; Liu, Chujun; Xiong, Jingwei; Cao, Huiqing; Liang, Zicai (2016-03-18). "Small activating RNA binds to the genomic target site in a seed-region-dependent manner". Nucleic Acids Research. 44 (5): 2274–2282. doi:10.1093/nar/gkw076. ISSN 1362-4962. PMC 4797303. PMID 26873922.{{cite journal}}: CS1 maint: PMC format (link)
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  15. ^ Voutila, Jon; Reebye, Vikash; Roberts, Thomas C.; Protopapa, Pantelitsa; Andrikakou, Pinelopi; Blakey, David C.; Habib, Robert; Huber, Hans; Saetrom, Pal (2017-08-04). "Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer". Molecular Therapy: The Journal of the American Society of Gene Therapy. doi:10.1016/j.ymthe.2017.07.018. ISSN 1525-0024. PMID 28882451.
  16. ^ Place, Robert F.; Li, Long-Cheng; Pookot, Deepa; Noonan, Emily J.; Dahiya, Rajvir (2008). "MicroRNA-373 induces expression of genes with complementary promoter sequences". Proceedings of the National Academy of Sciences. 105 (5): 1608–13. doi:10.1073/pnas.0707594105. PMC 2234192. PMID 18227514.[non-primary source needed]
  17. ^ Huang, Vera; Place, Robert F.; Portnoy, Victoria; Wang, Ji; Qi, Zhongxia; Jia, Zhejun; Yu, Angela; Shuman, Marc; et al. (2011). "Upregulation of Cyclin B1 by miRNA and its implications in cancer". Nucleic Acids Research. 40 (4): 1695–707. doi:10.1093/nar/gkr934. PMC 3287204. PMID 22053081.[non-primary source needed]
  18. ^ Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Manoharan, Muthiah; Corey, David R.; Janowski, Bethany A. (December 2013). "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.{{cite journal}}: CS1 maint: PMC format (link)
  19. ^ Dharap, Ashutosh; Pokrzywa, Courtney; Murali, Shruthi; Pandi, Gopal; Vemuganti, Raghu (2013). "MicroRNA miR-324-3p induces promoter-mediated expression of RelA gene". PloS One. 8 (11): e79467. doi:10.1371/journal.pone.0079467. ISSN 1932-6203. PMC 3827167. PMID 24265774.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  20. ^ a b c Chaluvally-Raghavan, Pradeep; Jeong, Kang Jin; Pradeep, Sunila; Silva, Andreia Machado; Yu, Shuangxing; Liu, Wenbin; Moss, Tyler; Rodriguez-Aguayo, Cristian; Zhang, Dong (2016-05-17). "Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer". Cell Reports. 15 (7): 1493–1504. doi:10.1016/j.celrep.2016.04.034. ISSN 2211-1247. PMC 4914391. PMID 27160903.{{cite journal}}: CS1 maint: PMC format (link)
  21. ^ Li, Senmao; Wang, Chenghe; Yu, Xiao; Wu, Huanlei; Hu, Jia; Wang, Shaogang; Ye, Zhangqun (January 2017). "miR-3619-5p inhibits prostate cancer cell growth by activating CDKN1A expression". Oncology Reports. 37 (1): 241–248. doi:10.3892/or.2016.5250. ISSN 1791-2431. PMID 27878260.
  22. ^ Xiao, Min; Li, Jin; Li, Wei; Wang, Yu; Wu, Feizhen; Xi, Yanping; Zhang, Lan; Ding, Chao; Luo, Huaibing (2016-02-06). "MicroRNAs activate gene transcription epigenetically as an enhancer trigger". RNA biology: 1–9. doi:10.1080/15476286.2015.1112487. ISSN 1555-8584. PMID 26853707.
  23. ^ Conine, Colin C.; Moresco, James J.; Gu, Weifeng; Shirayama, Masaki; Conte, Darryl; Yates, John R.; Mello, Craig C. (2013-12-19). "Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans". Cell. 155 (7): 1532–1544. doi:10.1016/j.cell.2013.11.032. ISSN 1097-4172. PMC 3924572. PMID 24360276.
  24. ^ Wedeles, CJ; Wu, MZ; Claycomb, JM (Dec 18, 2013). "Protection of Germline Gene Expression by the C. elegans Argonaute CSR-1". Developmental Cell. 27 (6): 664–71. doi:10.1016/j.devcel.2013.11.016. PMID 24360783.
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  27. ^ Kang, MR; Yang, G; Place, RF; Charisse, K; Epstein-Barash, H; Manoharan, M; Li, LC (Oct 1, 2012). "Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth". Cancer Research. 72 (19): 5069–79. doi:10.1158/0008-5472.can-12-1871. PMID 22869584.
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Further reading

External links

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