Progressive lengthening of 3' untranslated regions of mRNAs by alternative polyadenylation during C2C12 differentiation

The 3' untranslated regions (3' UTRs) of mRNAs contain cis-acting elements for posttranscriptional regulation of gene expression. Here, we report that mouse genes tend to express mRNAs with longer 3' UTRs as embryonic development progresses. This global regulation is controlled by alternative polyadenylation and coordinates with initiation of organogenesis and aspects of embryonic development, including morphogenesis, differentiation, and proliferation. Using myogenesis of C2C12 myoblast cells as a model, we recapitulated this process in vitro and found that 3' UTR lengthening is likely caused by weakening of mRNA polyadenylation activity. Because alternative 3' UTR sequences are typically longer and have higher AU content than constitutive ones, our results suggest that lengthening of 3' UTR can significantly augment posttranscriptional control of gene expression during embryonic development, such as microRNA-mediated regulation. Two biological replicates of C2C12 growth and differentiation conditions, repesctively信使RNA（mRNA）的3'非翻译区（3' untranslated regions，3' UTRs）包含参与基因表达转录后调控的顺式作用元件（cis-acting elements）。本研究发现，随着胚胎发育进程的推进，小鼠基因倾向于表达拥有更长3' UTR的mRNA。这种全局调控由可变聚腺苷酸化（alternative polyadenylation）介导，并与胚胎发育的器官发生（organogenesis）起始以及形态发生（morphogenesis）、细胞分化、细胞增殖等胚胎发育进程协同配合。本研究以C2C12成肌细胞（C2C12 myoblast cells）的肌发生（myogenesis）过程为模型，在体外（in vitro）重现了这一调控过程，并发现3' UTR延长可能源于mRNA聚腺苷酸化活性（polyadenylation activity）的减弱。由于可变3' UTR序列通常较组成型3' UTR更长，且AU含量更高，本研究结果表明，3' UTR延长可显著增强胚胎发育过程中基因表达的转录后调控，例如微小RNA（microRNA）介导的调控。本研究分别为C2C12细胞的生长与分化两种培养条件各设置了两份生物学重复。