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Regulation of Fibroblast Growth Factor-2 by an endogenous antisense RNA and by Argonaute-2

ABSTRACT: We have previously reported that elevated fibroblast growth factor-2 (FGF-2) expression is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer, and that these risks are reduced in tumors co-expressing an endogenous antisense (FGF-AS) RNA. In the present study we examined the role of the endogenous FGF-AS transcript in the regulation of FGF-2 expression in the human lung adenocarcinoma cell line, Seg-1. FGF-2 and FGF-AS were temporally and spatially co-localized in the cytoplasm of individual cells, and knock-down of either FGF-2 or FGF-AS by target specific siRNAs resulted in dose-dependent up-regulation of the complementary transcript and its encoded protein product. Using a luciferase reporter system we show that these effects are mediated by interaction of the endogenous antisense RNA with the 3’UTR of the FGF-2 mRNA. Deletion mapping identified a 392 nt sequence in the 5823 nucleotide FGF-2 untranslated tail which is targeted by FGF-AS. siRNA-mediated knockdown of either FGF-AS or FGF-2 significantly increased the stability of the complementary partner mRNA, demonstrating that these mRNAs are mutually regulatory. Knockdown of FGF-AS also resulted in reduced expression of argonaute-2 (AGO-2) and a number of other elements of the endogenous microRNA/RNAi pathways. Conversely, siRNA-mediated knockdown of AGO-2 significantly increased the stability of the FGF-2 mRNA transcript, and the steady-state levels of both FGF-2 mRNA and protein, suggesting a role for AGO-2 in the regulation of FGF-2 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20070 | GEO | 2010/01/28

SECONDARY ACCESSION(S): PRJNA124185

REPOSITORIES: GEO

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Project description:LlorénsRico2016 - Effects of cis-Encoded antisense RNAs (asRNAs) - Case1 Three putative effects of the asRNAs were considered in this study: in case 1 (this model) , the binding of the asRNA to the corresponding mRNA induces degradation of the duplex. In case 2, the binding of the asRNA to the mRNA induces degradation of the mRNA, but not of the asRNA. In case 3, the mRNA and the asRNA bind reversibly to form a stable duplex, preventing translation of the mRNA. In all the three cases, binding to the ribosome protects the mRNA from the effect of the asRNA. This model is described in the article: Bacterial antisense RNAs are mainly the product of transcriptional noise. Lloréns-Rico V, Cano J, Kamminga T, Gil R, Latorre A, Chen WH, Bork P, Glass JI, Serrano L, Lluch-Senar M. Sci Adv 2016 Mar; 2(3): e1501363 Abstract: cis-Encoded antisense RNAs (asRNAs) are widespread along bacterial transcriptomes. However, the role of most of these RNAs remains unknown, and there is an ongoing discussion as to what extent these transcripts are the result of transcriptional noise. We show, by comparative transcriptomics of 20 bacterial species and one chloroplast, that the number of asRNAs is exponentially dependent on the genomic AT content and that expression of asRNA at low levels exerts little impact in terms of energy consumption. A transcription model simulating mRNA and asRNA production indicates that the asRNA regulatory effect is only observed above certain expression thresholds, substantially higher than physiological transcript levels. These predictions were verified experimentally by overexpressing nine different asRNAs in Mycoplasma pneumoniae. Our results suggest that most of the antisense transcripts found in bacteria are the consequence of transcriptional noise, arising at spurious promoters throughout the genome. This model is hosted on BioModels Database and identified by: MODEL1511170000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:LlorénsRico2016 - Effects of cis-Encoded antisense RNAs (asRNAs) - Case3 Three putative effects of the asRNAs were considered in this study: in case 1, the binding of the asRNA to the corresponding mRNA induces degradation of the duplex. In case 2, the binding of the asRNA to the mRNA induces degradation of the mRNA, but not of the asRNA. In case 3 (this model), the mRNA and the asRNA bind reversibly to form a stable duplex, preventing translation of the mRNA. In all the three cases, binding to the ribosome protects the mRNA from the effect of the asRNA. This model is described in the article: Bacterial antisense RNAs are mainly the product of transcriptional noise. Lloréns-Rico V, Cano J, Kamminga T, Gil R, Latorre A, Chen WH, Bork P, Glass JI, Serrano L, Lluch-Senar M. Sci Adv 2016 Mar; 2(3): e1501363 Abstract: cis-Encoded antisense RNAs (asRNAs) are widespread along bacterial transcriptomes. However, the role of most of these RNAs remains unknown, and there is an ongoing discussion as to what extent these transcripts are the result of transcriptional noise. We show, by comparative transcriptomics of 20 bacterial species and one chloroplast, that the number of asRNAs is exponentially dependent on the genomic AT content and that expression of asRNA at low levels exerts little impact in terms of energy consumption. A transcription model simulating mRNA and asRNA production indicates that the asRNA regulatory effect is only observed above certain expression thresholds, substantially higher than physiological transcript levels. These predictions were verified experimentally by overexpressing nine different asRNAs in Mycoplasma pneumoniae. Our results suggest that most of the antisense transcripts found in bacteria are the consequence of transcriptional noise, arising at spurious promoters throughout the genome. This model is hosted on BioModels Database and identified by: MODEL1511170002. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Regulation of Fibroblast Growth Factor-2 by an endogenous antisense RNA and by Argonaute-2

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