Pan‐tissue analysis of allelic alternative polyadenylation suggests widespread functional regulation

• Published in: Molecular systems biology 2020-04, Vol.16 (4), p.e9367-n/a
• Main Authors: Li, Yisheng, Schaefke, Bernhard, Zou, Xudong, Zhang, Min, Heyd, Florian, Sun, Wei, Zhang, Bin, Li, Guipeng, Liang, Weizheng, He, Yuhao, Zhou, Juexiao, Li, Yunfei, Fang, Liang, Hu, Yuhui, Chen, Wei
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Alleles; alternative polyadenylation; Animals; Annotations; Cell Line; Coupling (molecular); Divergence; EMBO36; error hypothesis; Evolution; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation; Gene regulation; Genes; High-Throughput Nucleotide Sequencing; Hypotheses; Isoforms; Localization; Mice; Mice, Inbred Strains; Mouse Embryonic Stem Cells; neutral theory of molecular evolution; Polyadenylation; Proteins; regulatory evolution; Regulatory sequences; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stem cells; Tissue analysis; Tissue Distribution; Transcription
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20199367

Alternative polyadenylation (APA) is a major layer of gene regulation. However, it has recently been argued that most APA represents molecular noise. To clarify their functional relevance and evolution, we quantified allele‐specific APA patterns in multiple tissues from an F1 hybrid mouse. We found a clearly negative correlation between gene expression and APA diversity for the 2,866 genes (24.9%) with a dominant polyadenylation site (PAS) usage above or equal to 90%, suggesting that their other PASs represent molecular errors. Among the remaining genes with multiple PASs, 3,971 genes (34.5%) express two or more isoforms with potentially functional importance. Interestingly, the genes with potentially functional minor PASs specific to neuronal tissues often express two APA isoforms with distinct subcellular localizations. Furthermore, our analysis of cis ‐APA divergence shows its pattern across tissues is distinct from that of gene expression. Finally, we demonstrate that the relative usage of alternative PASs is not only affected by their cis ‐regulatory elements, but also by potential coupling between transcriptional and APA regulation as well as competition kinetics between alternative sites. Synopsis A comprehensive analysis of allele‐specific APA patterns is performed across several tissues of an F1 hybrid mouse. The study examines the potential functionality of APA diversity within and across tissues and the patterns of cis‐regulatory divergence between the two species. Differences between single‐PAS and multi‐PAS genes are not predicted by error hypothesis. A significant proportion of genes possess two or more potentially functional PASs which are often under tissue‐dependent regulation, whereas the error hypothesis only applies to a specific subset of multi‐PAS genes. Adaptive coupling between APA and transcriptional regulation favors increased major PAS usage with higher gene expression levels across tissues. The kinetics of competition between alternative PASs significantly contribute to the magnitude of divergence between alleles. Graphical Abstract A comprehensive analysis of allele‐specific APA patterns is performed across several tissues of an F1 hybrid mouse. The study examines the potential functionality of APA diversity within and across tissues and the patterns of cis‐regulatory divergence between the two species.