Genome-scale analysis of PCSK9 in PC12 cells reveals immune response modulation and alternative splicing of hypoxia response genes

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potential RNA regulatory protein that plays an important role in cholesterol and fatty acid metabolism; however, the genome-wide regulation of gene expression and alternative splicing of PCSK9 remain unclear. Methods: PCSK9 overexpression experiments were performed in rat PC12 cells, and 330 genes were differentially expressed, including 209 upregulated and 121 downregulated genes. Results: The genes regulated by PCSK9 were enriched in immune response-related pathways, which showed enriched CCL2, Cxcl1, and Irf9. Moreover, genes with altered splicing patterns regulated by PCSK9 overexpression were enriched in pathways including the hypoxic response, and the alternative splicing of PKM and ARNT changed significantly. Conclusions: We found that PCSK9 may participate in the progression of ischemic stroke by activating the immune/hypoxia response. Thus, this study extends the functional roles of PCSK9 in ischemic stroke pathogenesis. Significance: PCSK9 involved into the progression of ischemic stroke, which could considered as a therapeutic target for improving ischemic stroke. We developed a PCSK9 overexpression model in the PC12 cell line, coupled with RNA sequencing (RNA-seq), to comprehensively elucidate the biological functions of PCSK9 in PC12 cells and to examine alterations in transcriptional profiles following PCSK9 overexpression. Additionally, we performed comparative gene expression profiling analysis of RNA-seq data between PC12 cells and their PCSK9-overexpressing derivatives.