Dynamic alternative polyadenylation during iPSC differentiation into cardiomyocytes

Yanbo Yang; Xiaohong Wu; Wenqian Yang; Weiwei Jin; Dongyang Wang; Jianye Yang; Guanghui Jiang; Wen Zhang; Xiaohui Niu; Jing Gong

doi:10.1016/j.csbj.2022.10.025

Dynamic alternative polyadenylation during iPSC differentiation into cardiomyocytes

Comput Struct Biotechnol J. 2022 Oct 25:20:5859-5869. doi: 10.1016/j.csbj.2022.10.025. eCollection 2022.

Authors

Yanbo Yang¹, Xiaohong Wu¹, Wenqian Yang¹, Weiwei Jin¹, Dongyang Wang¹, Jianye Yang¹, Guanghui Jiang¹, Wen Zhang¹, Xiaohui Niu¹, Jing Gong^{1

2}

Affiliations

¹ Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
² College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China.

Abstract

Alternative polyadenylation (APA) is an important post-transcription regulatory mechanism widely occurring in eukaryotes and has been associated with special traits/diseases by several studies. However, the dynamic roles and patterns of APA in cell differentiation remain largely unknown. Here, we systematically characterized the APA profiles during the differentiation of induced pluripotent stem cells (iPSCs) to cardiomyocytes by the previously published RNA-seq data across 16 time points. We identified 950 differential APA events and found five dynamic APA patterns with fuzzy c-means clustering analysis. Among them, 3'UTR progressive lengthening is the main APA pattern over time, the genes of which are enriched in cell cycle and mRNA metabolic process pathways. By constructing the linear mixed-effects model, we also indicated that TIA1 plays an important role in regulating APA events with this pattern, including genes essential to cardiac function. Additionally, APA and polyA machinery activity with another pattern can immediately respond to developmental signal-mediated stimuli at the early differentiation stage and result in a sharp shortening of the 3'UTR. Finally, a miRNA-APA network is constructed and several hub miRNAs potentially regulating cardiomyocyte differentiation are detected. Our results show the complex APA mechanisms during the differentiation of iPSCs into cardiomyocytes and provide further insights for the understanding of APA regulation and cell differentiation.

Keywords: APA, Alternative polyadenylation; Alternative polyadenylation; Cardiomyocyte; Cell differentiation; Dynamic regulation; iPSCs, induced pluripotent stem cells; miRNA.