The transcriptional landscape of PPRE responsive genes in PKP2-cardiomyopathy

Abstract

This study investigates the molecular mechanisms of fatty acid oxidation (FAO) regulation in underlying arrhythmogenic cardiomyopathy associated with plakophilin-2 (PKP2-ACM). PKP2, as desmosomal gene, is crucial for cell adhesion in cardiomyocytes, and mutations in desmosomal genes can lead to cardiomyocyte detachment. PKP2-ACM heart contains fibrofatty tissue and presents lipid accumulation. These lipid abnormalities are the cause of a disrupted FAO pathway, which is regulated by the PPAR-RXR heterodimer by binding to the PPRE-motif to start transcription. We hypothesize that the expression of PPRE-responsive genes is altered in PKP2-ACM. However, no distinct list of cardiac specific PPRE-responsive genes is known. There a PPRE-responsive gene list was compiled through a semi-systematic search of epigenetic datasets, which yielded 26 PPRE-responsive genes. Moreover, the heart tissue distribution lipid abnormalities are not observed in all cells, skewing bulk RNA-seq analysis. Hence, we analyzed single-nucleus RNA sequencing (snRNA-seq) data of right ventricle heart tissue from PKP2-ACM patients and controls to identify cell type differences with altered expression patterns for the PPRE-responsive genes. Results showed significant differences in cell type abundance and gene expression of the PPRE-responsive genes between PKP2-ACM and controls. Specifically, specific PKP2-ACM cardiomyocytes exhibited limited expression of FAO genes, portraying a fibroblast like expression pattern. Upregulation of certain PPRE-responsive genes was observed in PKP2 cardiomyocytes suggesting a rescue effect for sustained heart function. Co-expression analysis yielded no significant results. In conclusion, PKP2-ACM is associated with altered expression of PPRE-responsive genes in specific sub type of cardiomyocytes, indicating a disruption in the FAO pathway and providing insights into the disease's molecular basis.