Gene Regulatory Network Analysis Defines Transcriptome Landscape with Alternative Splicing of Human Umbilical Vein Endothelial Cells during Replicative Senescence
Abstract BackgroundEndothelial cell senescence is the state of permanent cell cycle arrest and plays a critical role in the pathogenesis of age-related diseases. However, a comprehensive understanding of the gene regulatory network, including genome-wide alternative splicing machinery, involved in endothelial cell senescence is lacking.ResultsWe thoroughly described the transcriptome landscape of replicative senescent human umbilical vein endothelial cells. Genes showing a monotonic increase or decrease in expression with the culture period were defined as hub genes in the co-expression network. Computational network analysis of these genes led to the identification of canonical and non-canonical senescence pathways, such as MYC and SIRT2 signaling, which were down-regulated in metabolism and chromosome organization processes pathways. Additionally, we showed that endothelial cell senescence involves alternative splicing. Importantly, the first and last exon types of splicing, as observed in FLT1 and ACACA, were preferentially altered among the alternatively spliced genes during endothelial senescence. We further identified novel microexons in PRUNE2 and PSAP, each containing 9 nt, which were altered within the specific domain during endothelial senescence.ConclusionsThese findings unveil the comprehensive transcriptome pathway and novel signaling regulated by RNA processing, including gene expression and splicing, in replicative endothelial senescence.