Yang Yanbo, Wu Xiaohong, Yang Wenqian, Jin Weiwei, Wang Dongyang, Yang Jianye, Jiang Guanghui, Zhang Wen, Niu Xiaohui, Gong Jing
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China.
Comput Struct Biotechnol J. 2022 Oct 25;20:5859-5869. doi: 10.1016/j.csbj.2022.10.025. eCollection 2022.
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 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.
可变聚腺苷酸化（APA）是一种重要的转录后调控机制，广泛存在于真核生物中，多项研究已将其与特殊性状/疾病联系起来。然而，APA在细胞分化中的动态作用和模式仍 largely unknown。在此，我们通过先前发表的跨越16个时间点的RNA-seq数据，系统地描绘了诱导多能干细胞（iPSC）向心肌细胞分化过程中的APA图谱。我们鉴定出950个差异APA事件，并通过模糊c均值聚类分析发现了五种动态APA模式。其中，3'UTR渐进性延长是随时间变化的主要APA模式，其基因在细胞周期和mRNA代谢过程途径中富集。通过构建线性混合效应模型，我们还表明 在调节具有这种模式的APA事件中起重要作用，包括对心脏功能至关重要的基因。此外，具有另一种模式的APA和多聚腺苷酸化机制活性可在分化早期立即响应发育信号介导的刺激，并导致3'UTR急剧缩短。最后，构建了一个miRNA-APA网络，并检测到几个潜在调节心肌细胞分化的枢纽miRNA。我们的结果显示了iPSC向心肌细胞分化过程中复杂的APA机制，并为理解APA调控和细胞分化提供了进一步的见解。
