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Article ; Online: Sustained transgene expression from sleeping beauty DNA transposons containing a core fragment of the HNRPA2B1-CBX3 ubiquitous chromatin opening element (UCOE).

Skipper, Kristian Alsbjerg / Hollensen, Anne Kruse / Antoniou, Michael N / Mikkelsen, Jacob Giehm

BMC biotechnology

2019 Volume 19, Issue 1, Page(s) 75

Abstract: Background: DNA transposon-based vectors are effective nonviral tools for gene therapy and genetic engineering of cells. However, promoter DNA methylation and a near-random integration profile, which can result in transgene integration into ... ...

Abstract	Background: DNA transposon-based vectors are effective nonviral tools for gene therapy and genetic engineering of cells. However, promoter DNA methylation and a near-random integration profile, which can result in transgene integration into heterochromatin, renders such vectors vulnerable to transcriptional repression. Therefore, to secure persistent transgene expression it may be necessary to protect transposon-embedded transgenes with anti-transcriptional silencing elements. Results: We compare four different protective strategies in CHO-K1 cells. Our findings show robust protection from silencing of transgene cassettes mediated by the ubiquitous chromatin-opening element (UCOE) derived from the HNRPA2B1-CBX3 locus. Using a bioinformatic approach, we define a shorter HNRPA2B1-CBX3 UCOE core fragment and demonstrate that this can robustly maintain transgene expression after extended passaging of CHO-K1 cells carrying DNA transposon vectors equipped with this protective feature. Conclusions: Our findings contribute to the understanding of the mechanism of HNRPA2B1-CBX3 UCOE-based transgene protection and support the use of a correctly oriented core fragment of this UCOE for DNA transposon vector-based production of recombinant proteins in CHO-K1 cells.
MeSH term(s)	Animals ; CHO Cells ; Cricetinae ; Cricetulus ; DNA Methylation/genetics ; DNA Transposable Elements/genetics ; Promoter Regions, Genetic/genetics ; Transgenes/genetics
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2019-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1472-6750
ISSN (online)	1472-6750
DOI	10.1186/s12896-019-0570-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: circHIPK3 nucleates IGF2BP2 and functions as a competing endogenous RNA.

Okholm, Trine Line Hauge / Kamstrup, Andreas Bjerregaard / Nielsen, Morten Muhlig / Hollensen, Anne Kruse / Graversgaard, Mette Laugesen / Sørensen, Matilde Helbo / Kristensen, Lasse Sommer / Vang, Søren / Park, Samuel S / Yeo, Gene W / Dyrskjøt, Lars / Kjems, Jørgen / Pedersen, Jakob Skou / Damgaard, Christian Kroun

bioRxiv : the preprint server for biology

2024

Abstract: Circular RNAs (circRNAs) represent a class of widespread endogenous RNAs that regulate gene expression and thereby influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory ... ...

Abstract	Circular RNAs (circRNAs) represent a class of widespread endogenous RNAs that regulate gene expression and thereby influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Specifically, we use temporal depletion of circHIPK3 or specific RNA binding proteins (RBPs) and identify several perturbed genes by RNA sequencing analyses. Using expression-coupled motif analyses of mRNA expression data from various knockdown experiments, we identify an 11-mer motif within circHIPK3, which is also enriched in genes that become downregulated upon circHIPK3 depletion. By mining eCLIP datasets, we find that the 11-mer motif constitutes a strong binding site for IGF2BP2 and validate this circHIPK3-IGF2BP2 interaction experimentally using RNA-immunoprecipitation and competition assays in bladder cancer cell lines. Our results suggest that circHIPK3 and IGF2BP2 mRNA targets compete for binding. Since the identified 11-mer motif found in circHIPK3 is enriched in upregulated genes following IGF2BP2 knockdown, and since IGF2BP2 depletion conversely globally antagonizes the effect of circHIPK3 knockdown on target genes, our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.14.557527
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Article ; Online: Impaired STING Activation Due to a Variant in the E3 Ubiquitin Ligase AMFR in a Patient with Severe VZV Infection and Hemophagocytic Lymphohistiocytosis.

Thomsen, Michelle Mølgaard / Skouboe, Morten Kelder / Møhlenberg, Michelle / Zhao, Jian / de Keukeleere, Kerstin / Heinz, Johanna Laura / Werner, Marvin / Hollensen, Anne Kruse / Lønskov, Jonas / Nielsen, Ian / Carter-Timofte, Madalina Elena / Zhang, Baocun / Mikkelsen, Jacob Giehm / Fisker, Niels / Paludan, Søren R / Assing, Kristian / Mogensen, Trine H

Journal of clinical immunology

2024 Volume 44, Issue 2, Page(s) 56

Abstract: Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, causing two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, ... ...

Abstract	Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, causing two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy with stroke. Here, we describe a 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, hemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. Hemophagocytic lymphohistiocytosis (HLH) was strongly suspected and as the condition deteriorated, HLH therapy was initiated. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy. We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor (AMFR), encoding a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans. In conclusion, we describe a novel genetic etiology of severe VZV disease in childhood, also representing the first inborn error of immunity related to a defect in the cGAS-STING pathway.
MeSH term(s)	Child, Preschool ; Humans ; Chickenpox ; Herpes Zoster ; Herpesvirus 3, Human/genetics ; Immunity, Innate ; Interferon Type I ; Leukocytes, Mononuclear/metabolism ; Lymphohistiocytosis, Hemophagocytic/diagnosis ; Lymphohistiocytosis, Hemophagocytic/genetics ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Pneumonia ; Receptors, Autocrine Motility Factor ; Ubiquitin-Protein Ligases/genetics ; Male
Chemical Substances	AMFR protein, human (EC 2.3.2.27) ; Interferon Type I ; Nucleotidyltransferases (EC 2.7.7.-) ; Receptors, Autocrine Motility Factor (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2024-01-26
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-024-01653-5
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Article: Sustained transgene expression from sleeping beauty DNA transposons containing a core fragment of the HNRPA2B1-CBX3 ubiquitous chromatin opening element (UCOE)

Skipper, Kristian Alsbjerg / Hollensen, Anne Kruse / Antoniou, Michael N / Mikkelsen, Jacob Giehm

BMC biotechnology. 2019 Dec., v. 19, no. 1

2019

Abstract: BACKGROUND: DNA transposon-based vectors are effective nonviral tools for gene therapy and genetic engineering of cells. However, promoter DNA methylation and a near-random integration profile, which can result in transgene integration into ... ...

Abstract	BACKGROUND: DNA transposon-based vectors are effective nonviral tools for gene therapy and genetic engineering of cells. However, promoter DNA methylation and a near-random integration profile, which can result in transgene integration into heterochromatin, renders such vectors vulnerable to transcriptional repression. Therefore, to secure persistent transgene expression it may be necessary to protect transposon-embedded transgenes with anti-transcriptional silencing elements. RESULTS: We compare four different protective strategies in CHO-K1 cells. Our findings show robust protection from silencing of transgene cassettes mediated by the ubiquitous chromatin-opening element (UCOE) derived from the HNRPA2B1-CBX3 locus. Using a bioinformatic approach, we define a shorter HNRPA2B1-CBX3 UCOE core fragment and demonstrate that this can robustly maintain transgene expression after extended passaging of CHO-K1 cells carrying DNA transposon vectors equipped with this protective feature. CONCLUSIONS: Our findings contribute to the understanding of the mechanism of HNRPA2B1-CBX3 UCOE-based transgene protection and support the use of a correctly oriented core fragment of this UCOE for DNA transposon vector-based production of recombinant proteins in CHO-K1 cells.
Keywords	DNA ; DNA methylation ; bioinformatics ; gene expression ; gene therapy ; genetic engineering ; heterochromatin ; loci ; recombinant proteins ; transcription (genetics) ; transgenes ; transposons
Language	English
Dates of publication	2019-12
Size	p. 75.
Publishing place	BioMed Central
Document type	Article
ISSN	1472-6750
DOI	10.1186/s12896-019-0570-2
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Article ; Online: Box C/D snoRNP Autoregulation by a cis-Acting snoRNA in the NOP56 Pre-mRNA.

Lykke-Andersen, Søren / Ardal, Britt Kidmose / Hollensen, Anne Kruse / Damgaard, Christian Kroun / Jensen, Torben Heick

Molecular cell

2018 Volume 72, Issue 1, Page(s) 99–111.e5

Abstract: Box C/D snoRNAs constitute a class of abundant noncoding RNAs that associate with common core proteins to form catalytic snoRNPs. Most of these operate in trans to assist the maturation of rRNAs by guiding and catalyzing the 2'-O-methylation of specific ... ...

Abstract	Box C/D snoRNAs constitute a class of abundant noncoding RNAs that associate with common core proteins to form catalytic snoRNPs. Most of these operate in trans to assist the maturation of rRNAs by guiding and catalyzing the 2'-O-methylation of specific nucleotides. Here, we report that the human intron-hosted box C/D snoRNA snoRD86 acts in cis as a sensor and master switch controlling levels of the limiting snoRNP core protein NOP56, which is important for proper ribosome biogenesis. Our results support a model in which snoRD86 adopts different RNP conformations that dictate the usage of nearby alternative splice donors in the NOP56 pre-mRNA. Excess snoRNP core proteins prevent further production of NOP56 and instead trigger the generation of a cytoplasmic snoRD86-containing NOP56-derived lncRNA via the nonsense-mediated decay pathway. Our findings reveal a feedback mechanism based on RNA structure that controls the precise coordination between box C/D snoRNP core proteins and global snoRNA levels.
MeSH term(s)	Alternative Splicing/genetics ; Animals ; Cell Nucleolus/genetics ; HEK293 Cells ; Homeostasis/genetics ; Humans ; Introns/genetics ; Mice ; Nuclear Proteins/genetics ; Protein Binding ; RNA Precursors/genetics ; Rabbits ; Ribonucleoproteins, Small Nucleolar/genetics
Chemical Substances	NOP56 protein, human ; Nuclear Proteins ; RNA Precursors ; Ribonucleoproteins, Small Nucleolar
Language	English
Publishing date	2018-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2018.08.017
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Zs.A 5055: Show issues

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Article ; Online: Managing microRNAs with vector-encoded decoy-type inhibitors.

Bak, Rasmus O / Hollensen, Anne Kruse / Mikkelsen, Jacob Giehm

Molecular therapy : the journal of the American Society of Gene Therapy

2013 Volume 21, Issue 8, Page(s) 1478–1485

Abstract: A rapidly growing understanding of the complex circuitry of microRNA (miRNA)-mediated gene regulation is attracting attention to miRNAs as new drug targets. Targeted miRNA suppression is achieved in a sequence-specific manner by antisense RNA "decoy" ... ...

Abstract	A rapidly growing understanding of the complex circuitry of microRNA (miRNA)-mediated gene regulation is attracting attention to miRNAs as new drug targets. Targeted miRNA suppression is achieved in a sequence-specific manner by antisense RNA "decoy" molecules. Such synthetic miRNA inhibitors have reached the clinic with remarkable pace and may soon appear as new therapeutic modalities in several diseases. Shortcomings, however, include high production costs, the requirement for repeated administration, and difficulty achieving tissue-specific delivery. With the many recent landmark achievements in clinical gene therapy, new and refined vector-encoded miRNA suppression technologies are attractive for many applications, not least as tools in innumerable daily studies of miRNA biology in laboratories worldwide. Here, we provide an overview of the strategies that have been used to adapt vector-encoded inhibitors for miRNA suppression and discuss advantages related to spatiotemporal and long-term miRNA attenuation. With the remarkable new discovery of miRNA management by naturally occurring circular RNAs, RNA circles generated by trans-splicing mechanisms may prove to be well-suited carriers of decoy-type miRNA inhibitors. The community will aspire to combine circles with high-affinity miRNA decoy methodologies, and such "vectorized" RNA circles may represent new solid ways to deliver miRNA inhibitors, perhaps even with therapeutic applications.
MeSH term(s)	Animals ; Gene Expression Regulation ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors/genetics ; Humans ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/genetics ; Organ Specificity ; RNA ; RNA Interference ; RNA, Antisense/genetics ; RNA, Antisense/metabolism ; RNA, Circular ; Trans-Splicing
Chemical Substances	MicroRNAs ; RNA, Antisense ; RNA, Circular ; RNA (63231-63-0)
Language	English
Publishing date	2013-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1038/mt.2013.113
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Zs.A 5640: Show issues

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Article ; Online: circZNF827

Hollensen, Anne Kruse / Thomsen, Henriette Sylvain / Lloret-Llinares, Marta / Kamstrup, Andreas Bjerregaard / Jensen, Jacob Malte / Luckmann, Majbritt / Birkmose, Nanna / Palmfeldt, Johan / Jensen, Torben Heick / Hansen, Thomas B / Damgaard, Christian Kroun

eLife

2020 Volume 9

Abstract: Circular RNAs are important for many cellular processes but their mechanisms of action remain poorly understood. Here, we map circRNA inventories of mouse embryonic stem cells, neuronal progenitor cells and differentiated neurons and identify hundreds of ...

Abstract	Circular RNAs are important for many cellular processes but their mechanisms of action remain poorly understood. Here, we map circRNA inventories of mouse embryonic stem cells, neuronal progenitor cells and differentiated neurons and identify hundreds of highly expressed circRNAs. By screening several candidate circRNAs for a potential function in neuronal differentiation, we find that
MeSH term(s)	Animals ; Cell Differentiation ; Embryonic Stem Cells/metabolism ; Gene Knockdown Techniques ; Mice ; Neurons/metabolism ; RNA, Circular/metabolism ; Receptors, Retinoic Acid/metabolism ; Transcription, Genetic
Chemical Substances	RNA, Circular ; Receptors, Retinoic Acid
Language	English
Publishing date	2020-11-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.58478
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Article ; Online: CDK1 couples proliferation with protein synthesis.

Haneke, Katharina / Schott, Johanna / Lindner, Doris / Hollensen, Anne Kruse / Damgaard, Christian Kroun / Mongis, Cyril / Knop, Michael / Palm, Wilhelm / Ruggieri, Alessia / Stoecklin, Georg

The Journal of cell biology

2020 Volume 219, Issue 3

Abstract: Cell proliferation exerts a high demand on protein synthesis, yet the mechanisms coupling the two processes are not fully understood. A kinase and phosphatase screen for activators of translation, based on the formation of stress granules in human cells, ...

Abstract	Cell proliferation exerts a high demand on protein synthesis, yet the mechanisms coupling the two processes are not fully understood. A kinase and phosphatase screen for activators of translation, based on the formation of stress granules in human cells, revealed cell cycle-associated kinases as major candidates. CDK1 was identified as a positive regulator of global translation, and cell synchronization experiments showed that this is an extramitotic function of CDK1. Different pathways including eIF2α, 4EBP, and S6K1 signaling contribute to controlling global translation downstream of CDK1. Moreover, Ribo-Seq analysis uncovered that CDK1 exerts a particularly strong effect on the translation of 5'TOP mRNAs, which includes mRNAs encoding ribosomal proteins and several translation factors. This effect requires the 5'TOP mRNA-binding protein LARP1, concurrent to our finding that LARP1 phosphorylation is strongly dependent on CDK1. Thus, CDK1 provides a direct means to couple cell proliferation with biosynthesis of the translation machinery and the rate of protein synthesis.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Autoantigens/genetics ; Autoantigens/metabolism ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Eukaryotic Initiation Factor-2/genetics ; Eukaryotic Initiation Factor-2/metabolism ; Eukaryotic Initiation Factors/genetics ; Eukaryotic Initiation Factors/metabolism ; Female ; Fibroblasts/enzymology ; Gene Expression Regulation, Enzymologic ; HEK293 Cells ; HeLa Cells ; Humans ; Kinetics ; Mice, Inbred C57BL ; Phosphorylation ; Protein Biosynthesis ; RNA 5' Terminal Oligopyrimidine Sequence ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Ribonucleoproteins/genetics ; Ribonucleoproteins/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/genetics ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction ; Uterine Cervical Neoplasms/enzymology ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/pathology ; SS-B Antigen
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autoantigens ; Cell Cycle Proteins ; EIF4EBP1 protein, human ; EIF4EBP2 protein, human ; Eukaryotic Initiation Factor-2 ; Eukaryotic Initiation Factors ; RNA, Messenger ; Ribonucleoproteins ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; ribosomal protein S6 kinase, 70kD, polypeptide 1 (EC 2.7.11.1) ; CDC2 Protein Kinase (EC 2.7.11.22) ; CDK1 protein, human (EC 2.7.11.22) ; Cdk1 protein, mouse (EC 2.7.11.22)
Language	English
Publishing date	2020-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201906147
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Article ; Online: Suppression of microRNAs by dual-targeting and clustered Tough Decoy inhibitors.

Hollensen, Anne Kruse / Bak, Rasmus O / Haslund, Didde / Mikkelsen, Jacob Giehm

RNA biology

2013 Volume 10, Issue 3, Page(s) 406–414

Abstract: MicroRNAs (miRNAs) are ubiquitous regulators of gene expression that contribute to almost any cellular process. Methods for managing of miRNA activity are attracting increasing attention in relation to diverse experimental and therapeutic applications. ... ...

Abstract	MicroRNAs (miRNAs) are ubiquitous regulators of gene expression that contribute to almost any cellular process. Methods for managing of miRNA activity are attracting increasing attention in relation to diverse experimental and therapeutic applications. DNA-encoded miRNA inhibitors expressed from plasmid or virus-based vectors provide persistent miRNA suppression and options of tissue-directed micromanaging. In this report, we explore the potential of exploiting short, hairpin-shaped RNAs for simultaneous suppression of two or more miRNAs. Based on the "Tough Decoy" (TuD) design, we create dual-targeting hairpins carrying two miRNA recognition sites and demonstrate potent co-suppression of different pairs of unrelated miRNAs by a single DNA-encoded inhibitor RNA. In addition, enhanced miRNA suppression is achieved by expression of RNA polymerase II-transcribed inhibitors carrying clustered TuD hairpins with up to a total of eight miRNA recognition sites. Notably, by expressing clustered TuD inhibitors harboring a single recognition site for each of a total of six miRNAs, we document robust parallel suppression of multiple miRNAs by inhibitor RNA molecules encoded by a single expression cassette. These findings unveil a new potential of TuD-based miRNA inhibitors and pave the way for standardizing synchronized suppression of families or clusters of miRNAs.
MeSH term(s)	Binding Sites ; Gene Expression Regulation ; Genetic Vectors ; HEK293 Cells ; Humans ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/metabolism ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism
Chemical Substances	MicroRNAs ; RNA, Small Interfering ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2013-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1555-8584
ISSN (online)	1555-8584
DOI	10.4161/rna.23543
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Article ; Online: Improved microRNA suppression by WPRE-linked tough decoy microRNA sponges.

Hollensen, Anne Kruse / Thomsen, Rune / Bak, Rasmus O / Petersen, Charlotte Christie / Ermegaard, Eva R / Aagaard, Lars / Damgaard, Christian Kroun / Mikkelsen, Jacob Giehm

RNA (New York, N.Y.)

2017 Volume 23, Issue 8, Page(s) 1247–1258

Abstract: Our genes are post-transcriptionally regulated by microRNAs (miRNAs) inducing translational suppression and degradation of targeted mRNAs. Strategies to inhibit miRNAs in a spatiotemporal manner in a desired cell type or tissue, or at a desired ... ...

Abstract	Our genes are post-transcriptionally regulated by microRNAs (miRNAs) inducing translational suppression and degradation of targeted mRNAs. Strategies to inhibit miRNAs in a spatiotemporal manner in a desired cell type or tissue, or at a desired developmental stage, can be crucial for understanding miRNA function and for pushing forward miRNA suppression as a feasible rationale for genetic treatment of disease. For such purposes, RNA polymerase II (RNA Pol II)-transcribed tough decoy (TuD) miRNA inhibitors are particularly attractive. Here, we demonstrate augmented miRNA suppression capacity of TuD RNA hairpins linked to the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). This effect is position-dependent and evident only when the WPRE is positioned upstream of the TuD. In accordance, inclusion of the WPRE does not change nuclear export, translation, total levels of TuD-containing RNA transcripts, or cytoplasmic P-body localization, suggesting that previously reported WPRE functions are negligible for improved TuD function. Notably, deletion analysis of TuD-fused WPRE unveils truncated WPRE variants resulting in optimized miRNA suppression. Together, our findings add to the guidelines for production of WPRE-supported anti-miRNA TuDs.
MeSH term(s)	Binding Sites ; Gene Expression Regulation ; Genetic Vectors ; HEK293 Cells ; Humans ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Promoter Regions, Genetic ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Regulatory Elements, Transcriptional
Chemical Substances	MicroRNAs ; RNA, Messenger ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.061192.117
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