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Article ; Online: Detection of microRNA-Target Interactions by Chimera PCR (ChimP).

Broughton, James P / Pasquinelli, Amy E

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1823, Page(s) 153–165

Abstract: MicroRNAs (miRNAs) regulate gene expression by directing Argonaute proteins to target RNAs, which usually results in destabilization and translational inhibition of the target RNA. The prediction of animal miRNA target sites has remained a challenge due ... ...

Abstract	MicroRNAs (miRNAs) regulate gene expression by directing Argonaute proteins to target RNAs, which usually results in destabilization and translational inhibition of the target RNA. The prediction of animal miRNA target sites has remained a challenge due to the ability of miRNAs to bind target RNAs through imperfect base pairing. Recently, several labs have established methods to produce biochemical evidence of miRNA-target interactions by generating chimeric reads where the miRNA is ligated to its target RNA. Despite the insights that can be gained from chimera producing methods, the current approaches are inefficient, labor intensive and require computational expertise. Here we describe a method, called Chimera PCR (ChimP), for the validation or testing of specific miRNA-target interactions. This method allows for focused experiments to analyze miRNA targeting in a variety of conditions.
MeSH term(s)	Animals ; Base Pairing ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; Polymerase Chain Reaction/methods ; RNA, Helminth/biosynthesis ; RNA, Helminth/genetics
Chemical Substances	MicroRNAs ; RNA, Helminth
Language	English
Publishing date	2018-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-8624-8_12
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Article ; Online: Performance of Patient-Reported Outcomes Measurement Information System (PROMIS) scores compared with legacy metrics in evaluating outcomes after surgical treatment for osteochondritis dissecans of the humeral capitellum.

Broughton, James Sam / Goldfarb, Charles A / Obey, Mitchel R / Smith, Matthew V

Journal of shoulder and elbow surgery

2021 Volume 30, Issue 7, Page(s) 1511–1518

Abstract: Background: Patient-Reported Outcomes Measurement Information System (PROMIS) scores have not previously been used to measure long-term outcomes in operatively treated capitellar osteochondritis dissecans (OCD) patients. The aims of our study were to (1) ...

Abstract	Background: Patient-Reported Outcomes Measurement Information System (PROMIS) scores have not previously been used to measure long-term outcomes in operatively treated capitellar osteochondritis dissecans (OCD) patients. The aims of our study were to (1) assess patients' long-term outcomes using PROMIS scores, (2) compare the performance of PROMIS with other validated elbow legacy metrics, and (3) evaluate ceiling and floor effects in these outcome measures in patients undergoing surgical treatment for capitellar OCD. Methods: We evaluated demographic characteristics, procedure details, preoperative PROMIS scores, and associated sports information in surgically treated pediatric capitellar OCD patients. An online survey was sent to the study participants, including the Kerlan-Jobe Orthopaedic Clinic (KJOC) shoulder and elbow score, the quick Disabilities of the Arm, Shoulder and Hand questionnaire, and the Liverpool Elbow Score patient-answered questionnaire, as well as the Mobility, Pain Interference, and Upper Extremity questionnaires from the PROMIS pediatrics bank. Correlations were evaluated between outcome measures. Ceiling and floor effects were evaluated for each outcome measure. Results: Completed surveys were obtained for 57 patients (59 elbows). The mean patient age at surgery was 14 years (range, 10-18 years). The mean follow-up time was 6 years (standard deviation, 5 years; range, 1-18 years). The mean PROMIS Mobility score improved from 41.2 preoperatively to 55.2 postoperatively (P < .001). The mean Pain Interference score decreased from 46.9 preoperatively to 38 postoperatively (P < .001). The mean Upper Extremity score improved from 42.7 preoperatively to 53.2 postoperatively (P < .001). Significant correlations were observed between all legacy metrics and postoperative PROMIS scores (\|r\| > 0.54, P < .001). Ceiling or floor effects were seen in all legacy metrics and PROMIS scores. The KJOC score was least affected by ceiling or floor effects. Conclusion: There is a strong correlation between PROMIS scores and legacy measures evaluating outcomes after surgical management of capitellar OCD. However, large ceiling and floor effects were present in all measures, likely owing to the favorable clinical results. The KJOC score was limited the least by ceiling and floor effects.
MeSH term(s)	Benchmarking ; Child ; Humans ; Humerus ; Information Systems ; Osteochondritis Dissecans/surgery ; Patient Reported Outcome Measures
Language	English
Publishing date	2021-01-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1170782-3
ISSN	1532-6500 ; 1058-2746
ISSN (online)	1532-6500
ISSN	1058-2746
DOI	10.1016/j.jse.2020.11.032
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Article ; Online: A tale of two sequences: microRNA-target chimeric reads.

Broughton, James P / Pasquinelli, Amy E

Genetics, selection, evolution : GSE

2016 Volume 48, Page(s) 31

Abstract: In animals, a functional interaction between a microRNA (miRNA) and its target RNA requires only partial base pairing. The limited number of base pair interactions required for miRNA targeting provides miRNAs with broad regulatory potential and also ... ...

Abstract	In animals, a functional interaction between a microRNA (miRNA) and its target RNA requires only partial base pairing. The limited number of base pair interactions required for miRNA targeting provides miRNAs with broad regulatory potential and also makes target prediction challenging. Computational approaches to target prediction have focused on identifying miRNA target sites based on known sequence features that are important for canonical targeting and may miss non-canonical targets. Current state-of-the-art experimental approaches, such as CLIP-seq (cross-linking immunoprecipitation with sequencing), PAR-CLIP (photoactivatable-ribonucleoside-enhanced CLIP), and iCLIP (individual-nucleotide resolution CLIP), require inference of which miRNA is bound at each site. Recently, the development of methods to ligate miRNAs to their target RNAs during the preparation of sequencing libraries has provided a new tool for the identification of miRNA target sites. The chimeric, or hybrid, miRNA-target reads that are produced by these methods unambiguously identify the miRNA bound at a specific target site. The information provided by these chimeric reads has revealed extensive non-canonical interactions between miRNAs and their target mRNAs, and identified many novel interactions between miRNAs and noncoding RNAs.
MeSH term(s)	3' Untranslated Regions/genetics ; Animals ; Base Pairing ; Binding Sites ; Chimera/genetics ; Immunoprecipitation ; MicroRNAs/metabolism ; RNA/metabolism ; RNA, Untranslated/metabolism
Chemical Substances	3' Untranslated Regions ; MicroRNAs ; RNA, Untranslated ; RNA (63231-63-0)
Language	English
Publishing date	2016-04-04
Publishing country	France
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1005838-2
ISSN	1297-9686 ; 0754-0264 ; 0999-193X
ISSN (online)	1297-9686
ISSN	0754-0264 ; 0999-193X
DOI	10.1186/s12711-016-0209-x
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Article ; Online: Growth-dependent heterogeneity in the DNA damage response in Escherichia coli.

Jaramillo-Riveri, Sebastián / Broughton, James / McVey, Alexander / Pilizota, Teuta / Scott, Matthew / El Karoui, Meriem

Molecular systems biology

2022 Volume 18, Issue 5, Page(s) e10441

Abstract: In natural environments, bacteria are frequently exposed to sub-lethal levels of DNA damage, which leads to the induction of a stress response (the SOS response in Escherichia coli). Natural environments also vary in nutrient availability, resulting in ... ...

Abstract	In natural environments, bacteria are frequently exposed to sub-lethal levels of DNA damage, which leads to the induction of a stress response (the SOS response in Escherichia coli). Natural environments also vary in nutrient availability, resulting in distinct physiological changes in bacteria, which may have direct implications on their capacity to repair their chromosomes. Here, we evaluated the impact of varying the nutrient availability on the expression of the SOS response induced by chronic sub-lethal DNA damage in E. coli. We found heterogeneous expression of the SOS regulon at the single-cell level in all growth conditions. Surprisingly, we observed a larger fraction of high SOS-induced cells in slow growth as compared with fast growth, despite a higher rate of SOS induction in fast growth. The result can be explained by the dynamic balance between the rate of SOS induction and the division rates of cells exposed to DNA damage. Taken together, our data illustrate how cell division and physiology come together to produce growth-dependent heterogeneity in the DNA damage response.
MeSH term(s)	Bacterial Proteins/metabolism ; DNA Damage ; Escherichia coli/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; SOS Response, Genetics
Chemical Substances	Bacterial Proteins ; Escherichia coli Proteins
Language	English
Publishing date	2022-05-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.202110441
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Article: A tale of two sequences: microRNA-target chimeric reads

Broughton, James P / Amy E. Pasquinelli

Genetics, selection, evolution. 2016 Dec., v. 48, no. 1

2016

Abstract	In animals, a functional interaction between a microRNA (miRNA) and its target RNA requires only partial base pairing. The limited number of base pair interactions required for miRNA targeting provides miRNAs with broad regulatory potential and also makes target prediction challenging. Computational approaches to target prediction have focused on identifying miRNA target sites based on known sequence features that are important for canonical targeting and may miss non-canonical targets. Current state-of-the-art experimental approaches, such as CLIP-seq (cross-linking immunoprecipitation with sequencing), PAR-CLIP (photoactivatable-ribonucleoside-enhanced CLIP), and iCLIP (individual-nucleotide resolution CLIP), require inference of which miRNA is bound at each site. Recently, the development of methods to ligate miRNAs to their target RNAs during the preparation of sequencing libraries has provided a new tool for the identification of miRNA target sites. The chimeric, or hybrid, miRNA-target reads that are produced by these methods unambiguously identify the miRNA bound at a specific target site. The information provided by these chimeric reads has revealed extensive non-canonical interactions between miRNAs and their target mRNAs, and identified many novel interactions between miRNAs and noncoding RNAs.
Keywords	animals ; crosslinking ; DNA libraries ; hybrids ; messenger RNA ; microRNA ; non-coding RNA ; precipitin tests ; prediction
Language	English
Dates of publication	2016-12
Size	p. 31.
Publishing place	BioMed Central
Document type	Article
Note	Review
ZDB-ID	1005838-2
ISSN	1297-9686 ; 0754-0264 ; 0999-193X
ISSN (online)	1297-9686
ISSN	0754-0264 ; 0999-193X
DOI	10.1186/s12711-016-0209-x
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Article ; Online: Identifying Argonaute binding sites in Caenorhabditis elegans using iCLIP.

Broughton, James P / Pasquinelli, Amy E

Methods (San Diego, Calif.)

2013 Volume 63, Issue 2, Page(s) 119–125

Abstract: The identification of endogenous targets remains an important challenge in understanding microRNA (miRNA) function. Past approaches using in silico methods and reporter constructs lack biological context that may enhance or inhibit target recognition. To ...

Abstract	The identification of endogenous targets remains an important challenge in understanding microRNA (miRNA) function. Past approaches using in silico methods and reporter constructs lack biological context that may enhance or inhibit target recognition. To address these limitations, several labs have utilized crosslinking and immunoprecipitation (CLIP) of Argonaute (Ago) proteins to identify miRNA targets. Recently, the Ule Lab introduced individual-nucleotide resolution CLIP (iCLIP) to increase the sensitivity of identifying protein-RNA interaction sites. Here we adapt the iCLIP protocol for use in Caenorhabditis elegans to identify endogenous sites targeted by the worm Argonaute (ALG-1) primarily responsible for miRNA function.
MeSH term(s)	Animals ; Argonaute Proteins/isolation & purification ; Argonaute Proteins/metabolism ; Base Sequence ; Binding Sites ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/isolation & purification ; Caenorhabditis elegans Proteins/metabolism ; DNA Primers/genetics ; Immunoprecipitation/methods ; MicroRNAs/genetics ; MicroRNAs/isolation & purification ; MicroRNAs/metabolism ; Molecular Sequence Data ; RNA Interference ; RNA-Binding Proteins/isolation & purification ; RNA-Binding Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	ALG-1 protein, C elegans ; Argonaute Proteins ; Caenorhabditis elegans Proteins ; DNA Primers ; MicroRNAs ; RNA-Binding Proteins
Language	English
Publishing date	2013-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2013.03.033
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Article: Identifying Argonaute binding sites in Caenorhabditis elegans using iCLIP

Broughton, James P / Pasquinelli, Amy E

Methods. 2013 Sept. 15, v. 63, no. 2

2013

Abstract	The identification of endogenous targets remains an important challenge in understanding microRNA (miRNA) function. Past approaches using in silico methods and reporter constructs lack biological context that may enhance or inhibit target recognition. To address these limitations, several labs have utilized crosslinking and immunoprecipitation (CLIP) of Argonaute (Ago) proteins to identify miRNA targets. Recently, the Ule Lab introduced individual-nucleotide resolution CLIP (iCLIP) to increase the sensitivity of identifying protein–RNA interaction sites. Here we adapt the iCLIP protocol for use in Caenorhabditis elegans to identify endogenous sites targeted by the worm Argonaute (ALG-1) primarily responsible for miRNA function.
Keywords	Caenorhabditis elegans ; binding sites ; crosslinking ; microRNA ; precipitin tests ; proteins
Language	English
Dates of publication	2013-0915
Size	p. 119-125.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2013.03.033
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Article ; Online: COVID-19 Variant Detection with a High-Fidelity CRISPR-Cas12 Enzyme.

Fasching, Clare L / Servellita, Venice / McKay, Bridget / Nagesh, Vaishnavi / Broughton, James P / Sotomayor-Gonzalez, Alicia / Wang, Baolin / Brazer, Noah / Reyes, Kevin / Streithorst, Jessica / Deraney, Rachel N / Stanfield, Emma / Hendriks, Carley G / Fung, Becky / Miller, Steve / Ching, Jesus / Chen, Janice S / Chiu, Charles Y

Journal of clinical microbiology

2022 Volume 60, Issue 7, Page(s) e0026122

Abstract: Laboratory tests for the accurate and rapid identification of SARS-CoV-2 variants can potentially guide the treatment of COVID-19 patients and inform infection control and public health surveillance efforts. Here, we present the development and ... ...

Abstract	Laboratory tests for the accurate and rapid identification of SARS-CoV-2 variants can potentially guide the treatment of COVID-19 patients and inform infection control and public health surveillance efforts. Here, we present the development and validation of a rapid COVID-19 variant DETECTR assay incorporating loop-mediated isothermal amplification (LAMP) followed by CRISPR-Cas12 based identification of single nucleotide polymorphism (SNP) mutations in the SARS-CoV-2 spike (S) gene. This assay targets the L452R, E484K/Q/A, and N501Y mutations, at least one of which is found in nearly all major variants. In a comparison of three different Cas12 enzymes, only the newly identified enzyme CasDx1 was able to accurately identify all targeted SNP mutations. An analysis pipeline for CRISPR-based SNP identification from 261 clinical samples yielded a SNP concordance of 97.3% and agreement of 98.9% (258 of 261) for SARS-CoV-2 lineage classification, using SARS-CoV-2 whole-genome sequencing and/or real-time RT-PCR as test comparators. We also showed that detection of the single E484A mutation was necessary and sufficient to accurately identify Omicron from other major circulating variants in patient samples. These findings demonstrate the utility of CRISPR-based DETECTR as a faster and simpler diagnostic method compared with sequencing for SARS-CoV-2 variant identification in clinical and public health laboratories.
MeSH term(s)	COVID-19/diagnosis ; COVID-19 Testing ; CRISPR-Cas Systems ; Clinical Laboratory Techniques/methods ; Humans ; Mutation ; SARS-CoV-2/genetics ; Sensitivity and Specificity
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	390499-4
ISSN	1098-660X ; 0095-1137
ISSN (online)	1098-660X
ISSN	0095-1137
DOI	10.1128/jcm.00261-22
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Article ; Online: Pairing beyond the Seed Supports MicroRNA Targeting Specificity.

Broughton, James P / Lovci, Michael T / Huang, Jessica L / Yeo, Gene W / Pasquinelli, Amy E

Molecular cell

2016 Volume 64, Issue 2, Page(s) 320–333

Abstract: To identify endogenous miRNA-target sites, we isolated AGO-bound RNAs from Caenorhabditis elegans by individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP), which fortuitously also produced miRNA-target chimeric reads. Through the ... ...

Abstract	To identify endogenous miRNA-target sites, we isolated AGO-bound RNAs from Caenorhabditis elegans by individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP), which fortuitously also produced miRNA-target chimeric reads. Through the analysis of thousands of reproducible chimeras, pairing to the miRNA seed emerged as the predominant motif associated with functional interactions. Unexpectedly, we discovered that additional pairing to 3' sequences is prevalent in the majority of target sites and leads to specific targeting by members of miRNA families. By editing an endogenous target site, we demonstrate that 3' pairing determines targeting by specific miRNA family members and that seed pairing is not always sufficient for functional target interactions. Finally, we present a simplified method, chimera PCR (ChimP), for the detection of specific miRNA-target interactions. Overall, our analysis revealed that sequences in the 5' as well as the 3' regions of a miRNA provide the information necessary for stable and specific miRNA-target interactions in vivo.
MeSH term(s)	Animals ; Base Pairing ; Base Sequence ; Binding Sites ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Exons ; Gene Expression Regulation ; Immunoprecipitation/methods ; Introns ; MicroRNAs/classification ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Protein Binding ; RNA, Helminth/genetics ; RNA, Helminth/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Nucleolar/genetics ; RNA, Small Nucleolar/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
Chemical Substances	ALG-1 protein, C elegans ; Caenorhabditis elegans Proteins ; MicroRNAs ; RNA, Helminth ; RNA, Long Noncoding ; RNA, Messenger ; RNA, Small Nucleolar ; RNA-Binding Proteins
Language	English
Publishing date	2016--20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2016.09.004
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Article ; Online: Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging.

Aalto, Antti P / Nicastro, Ian A / Broughton, James P / Chipman, Laura B / Schreiner, William P / Chen, Jerry S / Pasquinelli, Amy E

PLoS genetics

2018 Volume 14, Issue 6, Page(s) e1007379

Abstract: Argonaute (AGO) proteins partner with microRNAs (miRNAs) to target specific genes for post-transcriptional regulation. During larval development in Caenorhabditis elegans, Argonaute-Like Gene 1 (ALG-1) is the primary mediator of the miRNA pathway, while ... ...

Abstract	Argonaute (AGO) proteins partner with microRNAs (miRNAs) to target specific genes for post-transcriptional regulation. During larval development in Caenorhabditis elegans, Argonaute-Like Gene 1 (ALG-1) is the primary mediator of the miRNA pathway, while the related ALG-2 protein is largely dispensable. Here we show that in adult C. elegans these AGOs are differentially expressed and, surprisingly, work in opposition to each other; alg-1 promotes longevity, whereas alg-2 restricts lifespan. Transcriptional profiling of adult animals revealed that distinct miRNAs and largely non-overlapping sets of protein-coding genes are misregulated in alg-1 and alg-2 mutants. Interestingly, many of the differentially expressed genes are downstream targets of the Insulin/ IGF-1 Signaling (IIS) pathway, which controls lifespan by regulating the activity of the DAF-16/ FOXO transcription factor. Consistent with this observation, we show that daf-16 is required for the extended lifespan of alg-2 mutants. Furthermore, the long lifespan of daf-2 insulin receptor mutants, which depends on daf-16, is strongly reduced in animals lacking alg-1 activity. This work establishes an important role for AGO-mediated gene regulation in aging C. elegans and illustrates that the activity of homologous genes can switch from complementary to antagonistic, depending on the life stage.
MeSH term(s)	Animals ; Argonaute Proteins/physiology ; Caenorhabditis elegans/physiology ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Caenorhabditis elegans Proteins/physiology ; Forkhead Transcription Factors/physiology ; Gene Expression Regulation, Developmental ; Genes, Helminth ; Insulin/metabolism ; Insulin-Like Growth Factor I/metabolism ; Longevity/genetics ; MicroRNAs/physiology ; Mutation ; RNA, Helminth/physiology ; RNA-Binding Proteins/physiology ; Receptor, Insulin/genetics ; Receptor, Insulin/metabolism ; Signal Transduction/physiology
Chemical Substances	ALG-1 protein, C elegans ; ALG-2 protein, C elegans ; Argonaute Proteins ; Caenorhabditis elegans Proteins ; Forkhead Transcription Factors ; Insulin ; MicroRNAs ; RNA, Helminth ; RNA-Binding Proteins ; daf-16 protein, C elegans ; Insulin-Like Growth Factor I (67763-96-6) ; DAF-2 protein, C elegans (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2018-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1007379
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