Data_Sheet_1_MicroRNA 3′ ends shorten during adolescent brain maturation.pdf

MicroRNA (miRNA) dysregulation is well-documented in psychiatric disease, but miRNA dynamics remain poorly understood during adolescent and early adult brain maturation, when symptoms often first appear. Here, we use RNA sequencing to examine miRNAs and their mRNA targets in cortex and hippocampus from early-, mid-, and late-adolescent and adult mice. Furthermore, we use quantitative proteomics by tandem mass tag mass spectrometry (TMT-MS) to examine protein dynamics in cortex from the same subjects. We found that ~25% of miRNAs’ 3′ ends shorten with age due to increased 3′ trimming and decreased U tailing. Particularly, shorter but functionally competent isoforms (isomiRs) of miR-338-3p increase up to 10-fold during adolescence and only in brain. MiRNAs that undergo 3′ shortening exhibit stronger negative correlations with targets that decrease with age and stronger positive correlations with targets that increase with age, than miRNAs with stable 3′ ends. Increased 3′ shortening with age was also observed in available mouse and human miRNA-seq data sets, and stronger correlations between miRNAs that undergo shortening and their mRNA targets were observed in two of the three available data sets. We conclude that age-associated miRNA 3′ shortening is a well-conserved feature of postnatal brain maturation.

微小核糖核酸（miRNA，MicroRNA）的失调在精神类疾病中已有充分文献记载，但在青少年及成年早期脑成熟阶段——这一时期往往是精神症状首次出现的节点——miRNA的动态变化仍未得到充分阐释。本研究通过RNA测序技术，对早期青少年、中期青少年、晚期青少年及成年小鼠的大脑皮层与海马体中的miRNA及其信使RNA（mRNA）靶标进行了检测。此外，本研究采用串联质量标签质谱（TMT-MS）开展定量蛋白质组学分析，对同一批小鼠大脑皮层中的蛋白质动态变化进行了观测。研究发现，约25%的miRNA的3'端会随年龄增长而缩短，这一现象源于3'端剪切作用增强及U尾化修饰的减少。尤为值得关注的是，miR-338-3p的较短但功能完备的异构体（isomiRs）仅在大脑的青少年阶段可上调至初始水平的10倍。与3'端稳定的miRNA相比，发生3'端缩短的miRNA与随年龄表达下调的靶标呈现更强的负相关，与随年龄表达上调的靶标则呈现更强的正相关。在已公开的小鼠及人类miRNA测序数据集中，同样观察到随年龄增长而3'端缩短的现象；且在三份已公开数据集中的两份里，发生3'端缩短的miRNA与其mRNA靶标之间的相关强度更为显著。本研究最终得出结论：与年龄相关的miRNA 3'端缩短是产后脑成熟过程中一个高度保守的特征。