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Quantitative Transcriptomic Analysis of Control and FAM210A Knockout Hearts by Next Generation Sequencing

ABSTRACT: Purpose: Next-generation sequencing (NGS) provides the change of cellular pathways at the transcriptomic level. The overall goal for this research are to compare the transcriptome profiling by NGS in cardiomyocyte-specific FAM210A conditional knockout (cKO) hearts and control (Ctrl) hearts at two different time points and to evaluate the signaling pathways affected by FAM210A deficiency in the heart at the molecular level. Methods: Cardiac mRNA profiles of FAM210A cKO and Ctrl hearts were generated by deep sequencing in triplicate at the late stage (~10 weeks post Fam210a cKO by tamoxifen induction) and in quadruplicates at the early stage (~5 weeks post Fam210a cKO by tamoxifen induction). Results: Using an optimized data analysis workflow from the Genomic Research Center at the University of Rochester, we mapped ~30 millian sequence reads per sample to the mouse genome in the hearts of Ctrl and Fam210a cKO mice at both early and late stages. RNA-seq data comfirmed the knockout of FAM210A in the Fam210a cKO hearts. We identified differentially expressed genes at both early and late stages of FAM210A cKO heart compared with Ctrl hearts (adjust P valuse <0.05). Among upregulated genes, we observed enhanced integrated stress response (ISR) gene signature at both early and late stages in Fam210a cKO hearts compared with Ctrl hearts, including aminoacyl-tRNA synthetases, amino acid synthases, and one-carbon metabolic enzymes. The downregulated genes were not common between the two stages. At the early stage, the top enriched pathways include negative regulation of blood coagulation and wound healing and fatty acid metabolic process. In contrast, at the late stage, the major pathways include sulfide oxidation, glucose import, and mitochondrial ETC complex assembly. Conclusions: Our study provides the first detailed transcriptomic anslysis of cardiomyocyte specific knockout of Fam210a in the heart at two different time-points by NGS. The RNA-seq data reported here provide a framework for comparative investigation of expression profiles in the hearts of FAM210A cKO compared with Ctrl hearts. Based on our analysis, we conclude that ISR is persistently activated in Fam210a cKO hearts, which may be a pro-survival compensatory response caused by the dysfunction of mitochondria in Fam210a cKO hearts. ISR activation can reprogram global cap-dependent translation and cellular metabolism simultaneously.

ORGANISM(S): Mus musculus

PROVIDER: GSE195957 | GEO | 2023/02/01

REPOSITORIES: GEO

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Project description:Three major MAP kinase signaling cascades, ERK, p38 and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. In order to study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac specific and temporally regulated expression of activated mutants of Ras, MKK3 and MKK7, which are selective upstream activators for ERK, p38 and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 weeks) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes upon MAP kinase activation in adult hearts. These results provide an overview to both short term and long term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure. Experiment Overall Design:MHC-floxed-HRas-v12/MKK3bE/MKK7D transgenic mice were bred with MHC-Mer-Cre-Mer (MCM) mice (from Dr. J. Molkentin, Cincinnati Children's Hospital) to generate double transgenic animals harboring both floxed transgenes and Mer-Cre-Mer transgene. At 12 weeks of age the double transgenic mice and non-transgenic littermate controls were treated via i.p. injection of tamoxifen at a dosage of 20mg/kgBW once a day for 3 consecutive days as reported. The hearts were harvested at an early (4-7 days post first tamoxifen injection) and a late (2-4 weeks) time point. Left ventricles were dissected and rapidly frozen in liquid nitrogen and stored at -80C prior to protein and RNA analysis. Transcription profiling of

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Quantitative Transcriptomic Analysis of Control and FAM210A Knockout Hearts by Next Generation Sequencing

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