Heart RNA-Seq of cardiomyocyte-specific and inducible Prmt5 knockout mouse model, AVV9-ACADVL rescue
Our study introduces a novel animal model featuring a cardiomyocyte-specific, inducible knockout of the Prmt5. The primary aim of this model is to investigate the regulatory mechanisms of PRMT5, the main representative of type II PRMTs. We found that PRMT5 controls Acadvl mRNA splicing, and that disruptions in this regulation lead to loss of functional ACADVL and cardiac dysfunction. Importantly, we also show that maintained expression of ACADVL is cardioprotective highlighting a potential therapeutic strategy. The animal model was created using a conditional-ready allele of Prmt5 sourced from the European Mouse Mutant Archive (EMMA, specifically the B6Brd;B6N-Tyrc-Brd Atm1Brd Prmt5tm2a(EUCOMM)WtsiPrmt5 strain). To achieve a conditional knockout, the lacZ reporter was excised using flippase recombinase. The resulting Prmt5loxP/loxP mice were then bred with transgenic mice expressing an inducible Cre recombinase under the control of the alpha-myosin heavy chain promoter (alpha-MHC-MerCreMer), enabling deletion of Prmt5 in cardiomyocytes. To test the hypothesis that the cardiac phenotype was driven by downregulation of ACADVL, we use preventive treatment with AVV9-containing ACADVL cDNA sequence, which restores ACADVL protein expression (day 0). This treatment was followed with tamoxifen treatment from day 5 to day 17. On day 38, animals were treated with NaCl (control) or Isoprenaline (ISO) for 10 days. Moreover, this model allows the study of PRMT5 derived heart failure, and allowed us to determine which molecular pathways are related to the phenotype.
Our study introduces a novel animal model featuring a cardiomyocyte-specific, inducible knockout of the Prmt5. The primary aim of this model is to investigate the regulatory mechanisms of PRMT5, the main representative of type II PRMTs. We found that PRMT5 controls Acadvl mRNA splicing, and that disruptions in this regulation lead to loss of functional ACADVL and cardiac dysfunction. Importantly, we also show that maintained expression of ACADVL is cardioprotective highlighting a potential therapeutic strategy. The animal model was created using a conditional-ready allele of Prmt5 sourced from the European Mouse Mutant Archive (EMMA, specifically the B6Brd;B6N-Tyrc-Brd Atm1Brd Prmt5tm2a(EUCOMM)WtsiPrmt5 strain). To achieve a conditional knockout, the lacZ reporter was excised using flippase recombinase. The resulting Prmt5loxP/loxP mice were then bred with transgenic mice expressing an inducible Cre recombinase under the control of the alpha-myosin heavy chain promoter (alpha-MHC-MerCreMer), enabling deletion of Prmt5 in cardiomyocytes. To test the hypothesis that the cardiac phenotype was driven by downregulation of ACADVL, we use preventive treatment with AVV9-containing ACADVL cDNA sequence, which restores ACADVL protein expression (day 0). This treatment was followed with tamoxifen treatment from day 5 to day 17. On day 38, animals were treated with NaCl (control) or Isoprenaline (ISO) for 10 days. Moreover, this model allows the study of PRMT5 derived heart failure, and allowed us to determine which molecular pathways are related to the phenotype.
European Bioinformatics Institute