DOCSLIB.ORG

Small RNA and Transcriptional Upregulation Victoria Portnoy, Vera Huang, Robert F

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Small RNA and Transcriptional Upregulation Victoria Portnoy, Vera Huang, Robert F Advanced Review Small RNA and transcriptional upregulation Victoria Portnoy, Vera Huang, Robert F. Place and Long-Cheng Li∗ Small RNA molecules, such as microRNA and small interfering RNA, have emerged as master regulators of gene expression through their ability to suppress target genes in a phenomenon collectively called RNA interference (RNAi). There is growing evidence that small RNAs can also serve as activators of gene expression by targeting gene regulatory sequences. This novel mechanism, known as RNA activation (RNAa), appears to be conserved in at least mammalian cells and trig- gered by both endogenous and artificially designed small RNAs. RNAa depends on Argonaute proteins, but possesses kinetics distinct from that of RNAi. Epigenetic changes are associated with RNAa and may contribute to transcriptional activation of target genes, but the underlying mechanism remains elusive. Given the potential of RNAa as a molecular tool for studying gene function and as a therapeutic for dis- ease, further research is needed to completely elucidate its molecular mechanism in order to refine the rules for target selection and improve strategies for exploiting it therapeutically. 2011 John Wiley & Sons, Ltd. WIREs RNA 2011 DOI: 10.1002/wrna.90 INTRODUCTION positively, thereby composing the ‘yin and yang’ of the RNA-mediated gene-regulation network. he quest to manipulate gene expression at Recently, several classes of small RNA have been Twill has been a fascinating pursuit since shown to upregulate gene expression at the transcrip- the establishment of the central dogma of gene tional and/or epigenetic level.7–11 To describe such expression. The discovery of posttranscriptional RNA phenomena, the term RNAa (RNA activation) has interference (RNAi) has partially fulfilled this goal— been coined to distinguish it from RNAi.7 In this that is the ability to suppress the expression of any review, we discuss (1) the observations made so far gene using small double-stranded RNAs (dsRNAs). 1,2 on RNAa; (2) our current understanding of its mech- Since the initial discovery of RNAi, several other anism of action; and (3) its potential application both related mechanisms of gene silencing have been as a tool to study gene function and as a therapy for identified that occur at the levels of chromatin, disease. We also speculate on the possibility of RNAa DNA, transcription, mRNA, and translation, each 3–6 being mediated by endogenous small noncoding RNA triggered by small RNA. It has been proposed (ncRNA). that RNAi is an evolutionarily conserved defense mechanism to suppress foreign sequences (i.e., viral infection); however, such examples are rare in higher SMALL dsRNA-MEDIATED eukaryotes despite the presence of intact RNAi TRANSCRIPTIONAL ACTIVATION machinery. Therefore, it is now believed, instead, that (RNAa) evolution has adapted this innate defense mechanism as a means to regulate gene expression. In this The discovery of RNAa came as a surprise. In early regard, it is reasonable to suggest that RNA-mediated 2004, our group was interested in how aberrant DNA gene regulation may have evolved the capability methylation of promoter sequences was regulated in to regulate target sequences both negatively and cancer cells. It was speculated that ncRNA could induce sequence-specific DNA methylation, a phe- ∗Correspondence to: [email protected] nomenon that had been known to occur in plants 12 Department of Urology and Helen-Diller Comprehensive Cancer for over 10 years. At the time, our laboratory was Center, University of California San Francisco, San Francisco, CA, investigating epigenetic mechanisms of gene silencing, USA including DNA hypermethylation in gene promot- DOI: 10.1002/wrna.90 ers. One particular gene of interest was E-cadherin, a 2011 John Wiley & Sons, Ltd. Advanced Review wires.wiley.com/rna tumor suppressor gene silenced in several types of can- Definition, Observations, and Features cers. The E-cadherin promoter contains a typical CpG of RNAa island surrounding the transcription start site that, 13,14 Definition upon methylation, silences E-cadherin expression. The term RNAa was originally used to describe We sought to examine whether DNA methylation gene activation at the transcriptional level mediated could be induced at the E-cadherin promoter by expos- by small dsRNA designed to target gene promoter ing cells to synthetic small dsRNAs, the known trigger sequences.7 These dsRNAs, termed ‘small activating for RNAi. By implementing rational small interfering RNAs’ (saRNAs) to distinguish them from siRNAs, RNA (siRNA) design rules15 against the E-cadherin exert an effect opposite to that of RNAi. Similar to promoter sequence, two high-scoring targets at sites just outside the CpG island were selected for testing. the term RNAi, whose definition has been expanded When dsRNA for either target was transfected into the to describe both transcriptional and posttranscrip- prostate cancer PC-3 cell line, surprisingly, E-cadherin tional gene silencing mechanisms, RNAa may also expression was robustly upregulated instead of being be used to describe other related mechanisms by downregulated.7 This sparked subsequent identifica- which small RNAs positively regulate gene expres- tion of additional examples of RNAa [e.g., p21 and sion and the epigenome, including transcriptional vascular endothelial growth factor (VEGF) genes]7 activation via targeting the 3 flanking regions of (Table 1). Shortly thereafter, another group reported genes with small dsRNAs,26 piwi-interacting RNA activation of the progesterone receptor (PR) and major (piRNA)-mediated epigenetic activation,27 microRNA vault protein (MVP) genes by dsRNA,8 implying that (miRNA)-mediated translational activation,28,29 and the phenomenon could be a general mechanism of additional gene activation mechanisms yet to be gene regulation. discovered. TABLE 1 RNA activation examples Gene Symbol (alias) Full Name Species Target Location Trigger RNA References Ccnb1 Cyclin B1 Mouse Promoter saRNA/agRNA 11 CDH1 (E-cadherin) Cadherin 1, type 1, Human and nonhuman Promoter saRNA/agRNA 7, 9, 11, 16–18 E-cadherin (epithelial) primates and miRNA CDKN1A (p21) Cyclin-dependent kinase Human and nonhuman Promoter saRNA/agRNA 7, 11, 19–22 inhibitor 1A primates CSDC2 Cold shock Human Promoter miRNA 9 domain-containing protein C2 CXCR4 Chemokine (C–X–C motif) Rat Promoter saRNA/agRNA 11 receptor 4 KLF4 Kruppel-like ¨ factor 4 Human Promoter saRNA/agRNA 23 LDLR Low-density lipoprotein Human Promoter saRNA/agRNA 24 receptor MVP Major vault protein Human Promoter saRNA/agRNA 8 NKX3-1 NK3 homeobox 1 Nonhuman primates Promoter saRNA/agRNA 11 PAWR (PAR4) PRKC, apoptosis, WT1, Nonhuman primates Promoter saRNA/agRNA 11 regulator PGR (PR) Progesterone receptor Human Promoter and saRNA/agRNA 8, 25 3 terminus TP53 (p53) Tumor protein 53 Nonhuman primates Promoter saRNA/agRNA 11 VEGFA (VEGF) Vascular endothelial growth Human and nonhuman Promoter saRNA/agRNA 7, 11 factor A primates Vegfa (Vegf) Vascular endothelial growth Mouse Promoter shRNA 10 factor A WT1 Wilms tumor 1 Nonhuman primates Promoter saRNA/agRNA 11 agRNA, antigene RNA; miRNA, microRNA; saRNA, small activating RNA. 2011 John Wiley & Sons, Ltd. WIREs RNA Small RNA and transcriptional upregulation Promoter-Targeting RNAa For example, in a side-by-side comparison, p21 activa- In our initial studies, by testing six genes and designing tion by saRNA did not emerge until ∼48 h following one or two saRNA targets on the promoter of each saRNA transfection, while knockdown of two genes gene, three of the tested genes (E-cadherin, p21, and [male absent on the first (MOF) or E2F1] by siRNA VEGF) were activated by their respective saRNAs.7 was detectable as early as 6 h.32 Perhaps, the delay These saRNAs have a target size of 19 nt with 3 in RNAa activity reflects a more complex mechanism dTdT overhangs—an identical structure to standard with additional rate-limiting steps. Because RNAa is a siRNAs. They targeted locations on gene promoters nuclear process acting on gene transcription, acquiring ranging from −200 to −700 relative to the transcrip- access to the nucleus may be one of the rate-limiting tion start site. Soon after, the Corey group reported steps. Changes in chromatin structure associated with that synthetic dsRNAs, termed antigene RNAs (agR- RNAa may also contribute to the delayed kinetics. NAs) to distinguish them from siRNAs that target Another peculiar feature of RNAa is its pro- mRNA, targeting the promoter regions of PR and longed effect. After a single saRNA transfection, gene MVP activated the expression of their respective target activation can last for nearly 2 weeks in certain cell genes. These agRNAs also have a target size of 19 nt lines.7,32 The duration of PR gene activation demon- but they target sequences located on or near the tran- strated by the Corey group8 and of E-cadherin and scription start site, ranging from −56 to −2. Interest- p21 induction observed by our group7,32 is remarkably ingly, in the example of the PR gene, the agRNA PR11, similar, suggesting prolonged activation is a general which targets sequence −11/+8, robustly induced PR feature of RNAa. It is reasonable to speculate that gene expression in the MCF7 breast cancer cell line, such long-lasting gene activation is due to epigenetic but suppressed PR expression in the T47D cell line changes, which may persist well beyond the life of which has higher basal expression of PR compared saRNA molecules. In support, several types of epige- to MCF7 cells.8 In these studies, RNAa was observed netic changes have been associated with RNAa (see when the saRNA/agRNA was introduced into the cells the section Transcriptional Activation is Associated at concentrations ranging from 5 to 50 nM.7,8 Since with Epigenetic Changes). these initial reports, additional examples of promoter- targeting RNAa have been identified (Table 1). Complementarity Requirement of Guide-Target Sequences for RNAa Nonpromoter-Targeting RNAa Classic RNAi mediated by siRNA requires perfect Targeting genomic regions outside promoter complementarity between the siRNA and its cognate sequences may also affect gene transcription both mRNA sequence.
Load more

Recommended publications
  • Abou Alezz, Monah Characterization of the Genomic and Splicing Features of Long 51 Non-Coding Rnas Using Bioinformatics Approaches
    Posters A-Z Abou Alezz, Monah Characterization of the genomic and splicing features of long 51 non-coding RNAs using bioinformatics approaches Aguilera-Cortés, Paulina Identification of cellular lncRNAs associated to the HIV-1 genomic RNA 52 by interactome capture Ahram, Mamoun The androgen, dihydrotestosterone, induces chemoresistance of triple 53 negative breast cancer cells independent of ABCG2 and microRNA-328-3p Ahunbay, Esra Watching the self-catalyzed splicing of a group II intron with 54 single-molecule sensitivity Alemu, Endalkachew Integrated Global Mapping of miRNA:target-RNA Interactions 55 Ali, Tamer The lncRNA locus Handsdown regulates cardiac gene programs and is 56 essential for early mouse development Alzahrani, Salma Revisiting the sRNAome Under a Revised MicroRNA Annotation Criteria 57 Amorim, Marcella Dissecting the threshold-based readout of mobile small RNA gradients 58 Arnoldi, Michele SINEUPs technology: a new route to possibly treat 59 haploinsufficiency-induced Epilepsy and Autism Spectrum Disorders (ASDs) Azhikina, Tatyana Small RNA F6 influences Mycobacterium smegmatis entry into 60 dormancy EMBO | EMBL Symposium: The Non-Coding Genome Barasa, Sheila Olendo Long non-coding RNAs in High Grade Serous Ovarian Carcinoma 61 Behera, Alok LIN28 as a new drug target 62 Behrmann, Iris Modulation of the IL-6-Signaling Pathway in Liver Cells by miRNAs 63 Targeting gp130, JAK1, and/or STAT3 Bencurova, Petra Inhibition of miRNA-129-2-3p increases risk and severity of seizures in 64 developing brain Bica, Cecilia The emerging
    [Show full text]
  • Enhancer Rnas: Transcriptional Regulators and Workmates of Namirnas in Myogenesis
    Odame et al. Cell Mol Biol Lett (2021) 26:4 https://doi.org/10.1186/s11658-021-00248-x Cellular & Molecular Biology Letters REVIEW Open Access Enhancer RNAs: transcriptional regulators and workmates of NamiRNAs in myogenesis Emmanuel Odame , Yuan Chen, Shuailong Zheng, Dinghui Dai, Bismark Kyei, Siyuan Zhan, Jiaxue Cao, Jiazhong Guo, Tao Zhong, Linjie Wang, Li Li* and Hongping Zhang* *Correspondence: [email protected]; zhp@sicau. Abstract edu.cn miRNAs are well known to be gene repressors. A newly identifed class of miRNAs Farm Animal Genetic Resources Exploration termed nuclear activating miRNAs (NamiRNAs), transcribed from miRNA loci that and Innovation Key exhibit enhancer features, promote gene expression via binding to the promoter and Laboratory of Sichuan enhancer marker regions of the target genes. Meanwhile, activated enhancers pro- Province, College of Animal Science and Technology, duce endogenous non-coding RNAs (named enhancer RNAs, eRNAs) to activate gene Sichuan Agricultural expression. During chromatin looping, transcribed eRNAs interact with NamiRNAs University, Chengdu 611130, through enhancer-promoter interaction to perform similar functions. Here, we review China the functional diferences and similarities between eRNAs and NamiRNAs in myogen- esis and disease. We also propose models demonstrating their mutual mechanism and function. We conclude that eRNAs are active molecules, transcriptional regulators, and partners of NamiRNAs, rather than mere RNAs produced during enhancer activation. Keywords: Enhancer RNA, NamiRNAs, MicroRNA, Myogenesis, Transcriptional regulator Introduction Te identifcation of lin-4 miRNA in Caenorhabditis elegans in 1993 [1] triggered research to discover and understand small microRNAs’ (miRNAs) mechanisms. Recently, some miRNAs are reported to activate target genes during transcription via base pairing to the 3ʹ or 5ʹ untranslated regions (3ʹ or 5ʹ UTRs), the promoter [2], and the enhancer regions [3].
    [Show full text]
  • Mirna Goes Nuclear
    POINT-OF-VIEW RNA Biology 9:3, 1–5; March 2012; G 2012 Landes Bioscience miRNA goes nuclear Vera Huang and Long-Cheng Li Department of Urology and Helen-Diller Comprehensive Cancer Center, University of California—San Francisco; San Francisco, CA USA icroRNAs (miRNAs), defined as to target(s). miRNAs are convention- m 21–24 nucleotide non-coding ally regarded as negative regulators of RNAs, are important regulators of gene gene expression, mostly through post- expression. Initially, the functions of transcriptional events taking place in the miRNAs were recognized as post- cytoplasm. They are known to target transcriptional regulators on mRNAs complementary sequence on the mRNA that result in mRNA degradation and/or at different sites or on many different translational repression. It is becoming mRNAs through base-pairing between evident that miRNAs are not only the miRNA seed region and the 3' restricted to function in the cytoplasm, untranslated region (UTR) in the target they can also regulate gene expression in mRNA. It has been reported that other cellular compartments by a spec- miRNAs can also regulate gene expres- trum of targeting mechanisms via coding sion by targeting the 5' UTR,3 coding © 2012 Landesregions, 5' and 3'untransalated Bioscience. regions regions,4 promoters,5-8 and gene termini.9 (UTRs), promoters, and gene termini. In addition, miRNAs are predicted by In this point-of-view, we will speci- several genome-wide computational ana- fically focus on the nuclear functions lyses to target gene promoters because of miRNAs and discuss examples of potential targets for miRNAs are com- miRNA-directed transcriptional gene monly found based on sequence homo- regulation identified in recent years.
    [Show full text]
  • Mirna Activation Is an Endogenous Gene Expression Pathway
    RNA Biology ISSN: 1547-6286 (Print) 1555-8584 (Online) Journal homepage: http://www.tandfonline.com/loi/krnb20 miRNA activation is an endogenous gene expression pathway Dr. Luis M. Vaschetto To cite this article: Dr. Luis M. Vaschetto (2018): miRNA activation is an endogenous gene expression pathway, RNA Biology, DOI: 10.1080/15476286.2018.1451722 To link to this article: https://doi.org/10.1080/15476286.2018.1451722 Accepted author version posted online: 14 Mar 2018. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=krnb20 Publisher: Taylor & Francis Journal: RNA Biology DOI: https://doi.org/10.1080/15476286.2018.1451722 Title: miRNA activation is an endogenous gene expression pathway Author Dr. Luis M. Vaschetto*1,2 Affiliations 1 Instituto de Diversidad y Ecología Animal, Consejo Nacional de Investigaciones Científicas y Técnicas (IDEA, CONICET), Av. Vélez Sarsfield 299, X5000JJC Córdoba, Argentina. 2 Cátedra de Diversidad Animal I, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, (FCEFyN, UNC), Av. Vélez Sarsfield 299, X5000JJC Córdoba, Argentina. Corresponding author’s phone and e-mails Phone: 0054-3572- 445-6144 E-mails: [email protected] (primary e-mail); [email protected] Abstract Transfection of small non-coding RNAs (sncRNAs) molecules has become a routine technique widely used for silencing gene expression by triggering post- transcriptional and transcriptional RNA interference (RNAi) pathways. Moreover, in the past decade, small activating (saRNA) sequences targeting promoter regions were also reported, thereby a RNA-based gene activation (RNAa) mechanism has been proposed.
    [Show full text]
  • RNA Activation flew in the Face of at Dallas, Was Convinced She Had Messed Would Be Even More Unbelievable Than What Everyone’S Perceived Wisdom Regarding Something Up
    MODIFIED FROM ORIGINAL PHOTO. © 2009, THE ANN ARBOR NEWS. ALL RIGHTS RESERVED. REPRINTED WITH PERMISSION. fter getting the tion by as much as 90%.1 Interestingly, the other genes could also switch on gene data back from the findings confirmed work by Kevin Morris, mkZgl\kbimbhg'Ebd^<hk^rZg]CZghpldb% very first experi- now at the Scripps Research Institute in EbZg]IeZ\^p^k^^qi^\mbg`bgZ\mboZmbhg% ment at her new EZCheeZ%<Zeb_'%pahaZ]in[ebla^]ma^Öklm ghmma^hiihlbm^'ÊP^p^k^lnkikbl^]maZm job, Rosalyn Ram, evidence of this phenomenon in human we didn’t observe gene silencing by the a lab technician cells a year earlier. ]hn[e^&lmkZg]^]KG:%ËlZrlEb'ÊBglm^Z]% at the University ;nm<hk^rZg]CZghpldbZelhghmb\^] we observed strong gene activation.” of Texas Southwestern Medical Center something in their data that, if correct, RNA activation flew in the face of at Dallas, was convinced she had messed would be even more unbelievable than what everyone’s perceived wisdom regarding something up. The results were decidedly Ram saw on her first day at the bench. A few RNA-based regulation. RNA was thought Êp^bk]%Ëla^k^\Zeel'A^keZ[a^Z]l%ma^ h_<hk^rZg]CZghpldbÍll^^fbg`erÊbgZ\- to silence genes only by cutting up mRNA husband-and-wife research duo David tive” RNAs that did not reduce gene expres- via the RNAi pathway, not at the point <hk^rZg];^maZgrCZghpldb%aZ]Zek^Z]r sion reproducibly enhanced transcription of gene transcription and definitely not shown that synthetic DNA molecules with by around 25% to 50%.
    [Show full text]
  • Small Activating Rnas: Towards the Development of New Therapeutic Agents and Clinical Treatments
    cells Review Small Activating RNAs: Towards the Development of New Therapeutic Agents and Clinical Treatments Hossein Ghanbarian 1,2, Shahin Aghamiri 3 , Mohamad Eftekhary 2 , Nicole Wagner 4,*,† and Kay-Dietrich Wagner 4,*,† 1 Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19857-17443, Iran; [email protected] 2 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran; [email protected] 3 Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran; [email protected] 4 Université Côte d’Azur, CNRS, INSERM, iBV, 06107 Nice, France * Correspondence: [email protected] (N.W.); [email protected] (K.-D.W.); Tel.: +33-493-3776-65 (K.-D.W.) † Equal Contribution. Abstract: Small double-strand RNA (dsRNA) molecules can activate endogenous genes via an RNA-based promoter targeting mechanism. RNA activation (RNAa) is an evolutionarily conserved mechanism present in diverse eukaryotic organisms ranging from nematodes to humans. Small acti- vating RNAs (saRNAs) involved in RNAa have been successfully used to activate gene expression in cultured cells, and thereby this emergent technique might allow us to develop various biotechnologi- cal applications, without the need to synthesize hazardous construct systems harboring exogenous Citation: Ghanbarian, H.; Aghamiri, S.; Eftekhary, M.; Wagner, N.; Wagner, DNA sequences. Accordingly, this thematic issue aims to provide insights into how RNAa cellular K.-D. Small Activating RNAs: machinery can be harnessed to activate gene expression leading to a more effective clinical treatment Towards the Development of New of various diseases.
    [Show full text]
  • RNA Activation: a Diamond in the Rough for Genome Engineers†
    Letter to the Editor RNA activation: a diamond in the rough for genome engineers† Running title: RNA activation Dr. Luis María Vaschetto*1,2 Affiliations 1 Instituto de Diversidad y Ecología Animal, Consejo Nacional de Investigaciones Científicas y Técnicas (IDEA, CONICET), Av. Vélez Sarsfield 299, X5000JJC Córdoba, Argentina. 2 Cátedra de Diversidad Animal I, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, (FCEFyN, UNC), Av. Vélez Sarsfield 299, X5000JJC Córdoba, Argentina. Corresponding author’s phone and e-mails Phone: 0054-3572- 445-6144 E-mails: [email protected] (primary e-mail); [email protected] †This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: [10.1002/jcb.26228] Received 6 May 2017; Revised 18 June 2017; Accepted 20 June 2017 Journal of Cellular Biochemistry This article is protected by copyright. All rights reserved DOI 10.1002/jcb.26228 This article is protected by copyright. All rights reserved Abstract The ability to develop efficient and versatile technologies for manipulating gene expression is a fundamental issue both in biotechnology and therapeutics. The endogenous RNA interference (RNAi) pathway which mediates gene silencing was discovered at the end of the 20th century and it is nowadays considered as an essential strategy for knockdown of specific genes and for studying gene function. Remarkably, during the past decade, a RNA-induced mechanism of gene activation has also been reported.
    [Show full text]
  • Mireya: a Computational Approach to Detect Mirna- Directed Gene Activation [Version 2; Peer Review: 1 Approved, 2 Approved with Reservations]
    F1000Research 2021, 10:249 Last updated: 01 SEP 2021 SOFTWARE TOOL ARTICLE MIREyA: a computational approach to detect miRNA- directed gene activation [version 2; peer review: 1 approved, 2 approved with reservations] Anna Elizarova 1,2, Mumin Ozturk3,4, Reto Guler3-5, Yulia A. Medvedeva1,2 1Group of Regulatory Transcriptomics and Epigenomics, Research Center of Biotechnology, Institute of Bioengineering, Russian Academy of Sciences, Moscow, 117312, Russian Federation 2Department of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Dolgoprudny, 141701, Russian Federation 3International Centre for Genetic Engineering and Biotechnology, Cape Town, Cape Town, 7925, South Africa 4Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, Cape Town, 7925, South Africa 5Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, 7925, South Africa v2 First published: 29 Mar 2021, 10:249 Open Peer Review https://doi.org/10.12688/f1000research.28142.1 Latest published: 26 Aug 2021, 10:249 https://doi.org/10.12688/f1000research.28142.2 Reviewer Status Invited Reviewers Abstract Emerging studies demonstrate the ability of microRNAs (miRNAs) to 1 2 3 activate genes via different mechanisms. Specifically, miRNAs may trigger an enhancer promoting chromatin remodelling in the version 2 enhancer region, thus activating the enhancer and its target genes. (revision) report Here we present MIREyA, a pipeline developed to predict such miRNA- 26 Aug 2021 gene-enhancer trios based on an expression dataset which obviates the need to write custom scripts.
    [Show full text]
  • Development of MTL-CEPBA: Sarna Drug for Liver Disease
    Send Orders for Reprints to [email protected] Journal Name, Year, Volume 1 Development of MTL-CEPBA: SaRNA drug for Liver Disease Helen L Lightfoot†a, Ryan L Setten†b,c, John J Rossib,c and Nagy A Habibd* aMiNA Therapeutics Limited, Translation & Innovation Hub, 80 Wood Lane, London, W12 0BZ, United Kingdom; bDepartment of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA; cIrell & Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA; dDepartment of Surgery and Cancer, Imperial College London, London, UK. †authors contributed equally Abstract: Oligonucleotide drug development has revolutionised the drug discovery field allowing the notorious “undruggable” genome to become “druggable”. Of course, as with all, there are caveats to this new technology, which include restricted delivery and mode of actions – such drugs usually alter splicing and reduce RNA at the post- transcriptional level. Small activating RNA (saRNA)-mediated gene activation has opened a new potential therapeutic avenue for oligonucleotide drugs. SaRNAs promote endogenous transcription, a phenomenon known as RNA activation (RNAa), hence they function to increase gene expression levels. SaRNA based oligonucleotide therapeutics present great promise in expanding the “druggable” genome, with particular areas of interest including transcription factor activation and haploinsufficency. In this mini-review, we describe the pre-clinical development of the first saRNA drug to enter the clinic. This saRNA, referred to as MTL-CEPBA, targets the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα), a tumour suppressor and critical regulator of hepatocyte function. MTL-CEPBA is presently in Phase I clinical trials for hepatocellularcarcinoma (HCC).
    [Show full text]
  • Nucleoside Modifications Suppress RNA Activation of Cytoplasmic RNA Sensors
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Fall 2010 Nucleoside Modifications Suppress RNA Activation of Cytoplasmic RNA Sensors Bart R. Anderson University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Molecular Biology Commons Recommended Citation Anderson, Bart R., "Nucleoside Modifications Suppress RNA Activation of Cytoplasmic RNA Sensors" (2010). Publicly Accessible Penn Dissertations. 1567. https://repository.upenn.edu/edissertations/1567 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1567 For more information, please contact [email protected]. Nucleoside Modifications Suppress RNA Activation of Cytoplasmic RNA Sensors Abstract Multiple innate defense pathways exist to recognize and defend against foreign nucleic acids. Unlike innate immune receptors that recognize structures specific for pathogens that are not shared by mammalian hosts — for example, toll-like receptor (TLR)4-lipopolysaccharide, TLR5-flagellin, NOD1 and 2-peptidoglycan — all nucleic acids are made from four components that are identical from bacteria to man. Nucleoside modifications are prevalent in nature but vary greatly in their distribution and frequency, and therefore could serve as patterns for recognition of pathogenic nucleic acids. The presence of modified nucleosides in RNA reduces the activation of RNA-sensing TLRs and retinoic acid inducible gene I (RIG-I), which initiate signaling
    [Show full text]
  • Current Pharmaceutical Biotechnology, 2018, 19, 611-621 REVIEW ARTICLE
    Send Orders for Reprints to [email protected] 611 Current Pharmaceutical Biotechnology, 2018, 19, 611-621 REVIEW ARTICLE ISSN: 1389-2010 eISSN: 1873-4316 Current Pharmaceutical Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocel- Biotechnology Impact Factor: 1.819 The international lular Carcinoma journal for timely in-depth reviews in Pharmaceutical Biotechnology BENTHAM SCIENCE Ryan L. Setten†1,2, Helen L. Lightfoot†3, Nagy A. Habib4 and John J. Rossi1,2* 1Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA; 2Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA; 3MiNA Therapeutics Limited, Translation & Innovation Hub, 80 Wood Lane, London, W12 0BZ, United Kingdom; 4Department of Surgery and Cancer, Imperial College London, London, UK Abstract: Background: Oligonucleotide drug development has revolutionised the drug discovery field. Within this field, ‘small’ or ‘short’ activating RNAs (saRNA) are a more recently discovered category of short double-stranded RNA with clinical potential. saRNAs promote transcription from target loci, a phenomenon widely observed in mammals known as RNA activation (RNAa). Objective: The ability to target a particular gene is dependent on the sequence of the saRNA. Hence, A R T I C L E H I S T O R Y the potential clinical application of saRNAs is to increase target gene expression in a sequence-specific manner. saRNA-based therapeutics present opportunities for expanding the “druggable genome” with Received: January 20, 2018 particular areas of interest including transcription factor activation and cases of haploinsufficiency. Revised: May 30, 2018 Accepted: June 01, 2018 Results and Conclusion: In this mini-review, we describe the pre-clinical development of the first DOI: saRNA drug to enter the clinic.
    [Show full text]
  • Microrna in Control of Gene Expression: an Overview of Nuclear Functions
    International Journal of Molecular Sciences Review MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions Caterina Catalanotto *,†, Carlo Cogoni *,† and Giuseppe Zardo *,† Department of Cellular Biotechnologies and Hematology, University of Rome Sapienza, Rome 00179, Italy * Correspondence: [email protected] (Ca.Ca.); [email protected] (Ca.Co.); [email protected] (G.Z.); Tel.: +39-064-991-8247 (G.Z.); Fax: +39-064-991-8251 (G.Z.) † These authors contributed equally to this work. Academic Editor: Y-h. Taguchi Received: 26 August 2016; Accepted: 7 October 2016; Published: 13 October 2016 Abstract: The finding that small non-coding RNAs (ncRNAs) are able to control gene expression in a sequence specific manner has had a massive impact on biology. Recent improvements in high throughput sequencing and computational prediction methods have allowed the discovery and classification of several types of ncRNAs. Based on their precursor structures, biogenesis pathways and modes of action, ncRNAs are classified as small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs), promoter associate RNAs (pRNAs), small nucleolar RNAs (snoRNAs) and sno-derived RNAs. Among these, miRNAs appear as important cytoplasmic regulators of gene expression. miRNAs act as post-transcriptional regulators of their messenger RNA (mRNA) targets via mRNA degradation and/or translational repression. However, it is becoming evident that miRNAs also have specific nuclear functions. Among these, the most studied and debated activity is the miRNA-guided transcriptional control of gene expression. Although available data detail quite precisely the effectors of this activity, the mechanisms by which miRNAs identify their gene targets to control transcription are still a matter of debate.
    [Show full text]