Table_1_A post-transcriptional regulatory landscape of aging in the female mouse hippocampus.XLSX

Aging is associated with substantial physiological changes and constitutes a major risk factor for neurological disorders including dementia. Alterations in gene expression upon aging have been extensively studied; however, an in-depth characterization of post-transcriptional regulatory events remains elusive. Here, we profiled the age-related changes of the transcriptome and translatome in the female mouse hippocampus by RNA sequencing of total RNA and polysome preparations at four ages (3-, 6-, 12-, 20-month-old); and we implemented a variety of bioinformatics approaches to unravel alterations in transcript abundance, alternative splicing, and polyadenylation site selection. We observed mostly well-coordinated transcriptome and translatome expression signatures across age including upregulation of transcripts related to immune system processes and neuroinflammation, though transcripts encoding ribonucleoproteins or associated with mitochondrial functions, calcium signaling and the cell-cycle displayed substantial discordant profiles, suggesting translational control associated with age-related deficits in hippocampal-dependent behavior. By contrast, alternative splicing was less preserved, increased with age and was associated with distinct functionally-related transcripts encoding proteins acting at synapses/dendrites, RNA-binding proteins; thereby predicting regulatory roles for RBM3 and CIRBP. Only minor changes in polyadenylation site selection were identified, indicating pivotal 3′-end selection in young adults compared to older groups. Overall, our study provides a comprehensive resource of age-associated post-transcriptional regulatory events in the mouse hippocampus, enabling further examination of the molecular features underlying age-associated neurological diseases.

衰老伴随显著的生理变化，同时是包括痴呆在内的神经系统疾病的主要风险因素。衰老过程中基因表达的改变已被广泛研究，但转录后调控事件的深度表征仍不明晰。本研究通过对4个年龄阶段（3、6、12、20月龄）的雌性小鼠海马体总RNA及多聚核糖体制备样本进行RNA测序，解析了衰老相关的转录组（transcriptome）与翻译组（translatome）变化；并通过多种生物信息学方法，阐明了转录本丰度、可变剪接（alternative splicing）及多聚腺苷酸化位点选择（polyadenylation site selection）的改变。我们观察到各年龄阶段的转录组与翻译组表达特征整体协调一致，其中与免疫过程及神经炎症相关的转录本表达上调；但编码核糖核蛋白（ribonucleoproteins），或与线粒体功能、钙信号通路（calcium signaling）及细胞周期（cell-cycle）相关的转录本则呈现显著不一致的表达谱，这提示存在与海马依赖性行为衰老缺陷相关的翻译调控。与之相反，可变剪接的保守性较低，且随衰老进程增加，其与编码突触/树突相关蛋白、RNA结合蛋白（RNA-binding proteins）的功能特异性转录本相关；由此预测RBM3与CIRBP发挥调控作用。仅在多聚腺苷酸化位点选择中发现微小变化，这表明相较于老年组，年轻个体的3'端选择过程更为关键。总体而言，本研究为小鼠海马体中衰老相关的转录后调控事件提供了全面的资源，为进一步探究衰老相关神经系统疾病的分子特征提供了支持。