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Communication Dans Un Congrès Année : 2019

miRNA-processing pathway is impaired in skeletal muscle laminopathies

Résumé

MicroRNAs (miRNAs) are non-coding RNAs which regulate gene expression. They are synthesised as primary miRNAs (pri-miRNAs) which are subsequently cleaved into precursor miRNAs (pre-miRNAs) by DROSHA-DGCR8 complex. Pre-miRNAs are then exported into the cytoplasm by Exportin 5 where they are further processed by DICER into double stranded miRNAs. The mature miRNA strand is transferred to RISC complex which is guided to the target mRNA, leading to mRNA degradation or translation inhibition. Lamin A/C intermediate filaments, encoded by LMNA gene, are one of the components of the nuclear lamina, a protein meshwork underlying the inner nuclear envelope. They play a key role in nuclear resistance to mechanical stress, thus maintaining cell integrity, and they also regulate gene expression through interaction with chromatin, nuclear histones and transcription factors. It has been reported that miRNA transcriptome is altered in patients with laminopathies, a group of disorders due to mutations in lamin A/C, and in the presence of nuclear envelope abnormality, indicating that nuclear lamina might also be involved in miRNA regulation. Here we show that miRNA-processing pathway is dysregulated in laminopathy mouse model of LMNA-related Congenital Muscular Dystrophy mouse model harbouring a mutation found in patient (p.Lys32del). We found that miR-133-3p and miR-206-3p expression are altered in homozygous Lmna-delK32 myotubes. In order to determine which step of the miRNA-processing pathway is affected, we analysed the efficacy of shRNA and siRNA knockdown, that enter to the miRNA pathway after DROSHA-DGCR8 complex or after DICER, respectively. While siRNA knockdown was efficient, shRNA-mediated knockdown was not, indicating a defect in upstream miRNA-processing pathway in these cells. Overexpression of wild-type lamin A into homozygous Lmna-delK32 myotubes resulted in an improvement in shRNA efficiency suggesting that lamin A/C might have an important role in miRNA regulation
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Dates et versions

hal-03986899 , version 1 (13-02-2023)

Identifiants

  • HAL Id : hal-03986899 , version 1

Citer

Astrid Brull, Isabelle Nelson, Maud Beuvin, Gisèle Bonne, Anne T. Bertrand. miRNA-processing pathway is impaired in skeletal muscle laminopathies. 11TH EUROPEAN INTERMEDIATE FILAMENT MEETING EUROIF AND COST EUROCELLNET MEETING, Jun 2019, Turku, Finland. ⟨hal-03986899⟩
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