Increased intron retention is a post-transcriptional signature associated with progressive aging and Alzheimer's disease
Increased intron retention is a post-transcriptional signature associated with progressive aging and Alzheimer's disease
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DOI：
10.1111/acel.12928
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发表时间：
2019-06-01
期刊：
影响因子：
7.8
通讯作者：
Ong, Chin-Tong
中科院分区：
文献类型：
--
作者：
Adusumalli, Swarnaseetha;Ngian, Zhen-Kai;Ong, Chin-Tong
内含子保留（IR）通过选择性剪接是一种保守的调控机制，可以影响基因表达和蛋白质功能在成人发育和年龄发作性疾病。然而，目前还不清楚IR是否经历空间或时间的变化，在不同阶段的老化或神经退行性疾病，如阿尔茨海默病（AD）。通过分析不同年龄果蝇头细胞的转录组，我们观察到许多基因在衰老过程中IR事件显着增加。差异IR在不同年龄影响不同的生物学功能，并发生在老年人中的几个AD相关基因上。年轻动物差异保留内含子的核小体占有率增加表明它可能在衰老过程中调节IR水平。值得注意的是，在健康的老年小鼠和人脑组织中，以及在独立AD队列的小脑和额叶皮质中也观察到IR事件数量的增加。具有差异IR的基因具有许多共同特征，包括较短的内含子长度，其mRNA水平无扰动，以及与mRNA加工和蛋白质稳定相关的生物学功能的富集。在AD额叶皮层中鉴定的差异保留内含子具有较高的GC含量，与对照样品相比，其许多mRNA转录物显示出改变的蛋白质表达水平。总之，我们的结果表明，增加IR是一个保守的签名，与衰老有关。通过影响mRNA和蛋白质稳态的途径，IR模式在衰老过程中的变化可能会调节从健康到病理状态的迟发性散发性AD的过渡。
Intron retention (IR) by alternative splicing is a conserved regulatory mechanism that can affect gene expression and protein function during adult development and age-onset diseases. However, it remains unclear whether IR undergoes spatial or temporal changes during different stages of aging or neurodegeneration like Alzheimer's disease (AD). By profiling the transcriptome of Drosophila head cells at different ages, we observed a significant increase in IR events for many genes during aging. Differential IR affects distinct biological functions at different ages and occurs at several AD-associated genes in older adults. The increased nucleosome occupancy at the differentially retained introns in young animals suggests that it may regulate the level of IR during aging. Notably, an increase in the number of IR events was also observed in healthy older mouse and human brain tissues, as well as in the cerebellum and frontal cortex from independent AD cohorts. Genes with differential IR shared many common features, including shorter intron length, no perturbation in their mRNA level, and enrichment for biological functions that are associated with mRNA processing and proteostasis. The differentially retained introns identified in AD frontal cortex have higher GC content, with many of their mRNA transcripts showing an altered level of protein expression compared to control samples. Taken together, our results suggest that an increased IR is an conserved signature that is associated with aging. By affecting pathways involved in mRNA and protein homeostasis, changes of IR pattern during aging may regulate the transition from healthy to pathological state in late-onset sporadic AD.