生物信息学分析揭示了衰老加速小鼠 P8（SAMP8）老化大脑中的关键基因和途径。
Bioinformatic Analysis Reveals Key Genes and Pathways in Aging Brain of Senescence-accelerated Mouse P8 (SAMP8).
机构信息
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China.
College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China.
出版信息
CNS Neurol Disord Drug Targets. 2018;17(9):712-722. doi: 10.2174/1871527317666180816094741.
BACKGROUND
Aging is a complex process accompanied with the decline of the different physiological functions. Numerous differentially expressed genes (DEGs) have been found in the aging brain of senescence-accelerated mouse P8 (SAMP8), however, it was challenging to screen out the crucial ones.
OBJECTIVE
This study aimed to explore the crucial genes and pathways in aging brain of SAMP8 mice, which would be beneficial for understanding the pathogenesis of brain aging.
METHODS
Firstly, 430 genes that are differentially expressed in SAMP8 mice versus SAMR1 mice were obtained from 9 gene expression studies, and gene-gene network was constructed. Clustering analysis and topological analysis were used to single out the hub genes from this network. Secondly, pathway enrichment analysis was utilized to identify the key pathways from the 430 DEGs, and the DEGs in key pathways were considered as functional genes. Thirdly, the inner-network between hub genes and functional genes was constructed, and the key genes were predicted. Parts of the key genes were experimentally verified by quantitative real-time PCR (qRT-PCR), and the associated transcription factors (TFs) were predicted.
RESULTS
Our results revealed that 12 crucial genes might affect brain aging, including Trp53, Bcl2, Tnf, Casp9, Fos, Il6, Ptgs2, Il1b, Bdnf, Cdkn1a, Pik3c3, Rps6ka1, among which Casp9, Fos, Ptgs2, Cdkn1a, Pik3c3, and Rps6ka1 had been verified by qRT-PCR in 10-moth-old SAMP8 mice. Five functional groups including mitogen-activated protein kinase (MAPK) signaling pathway, neurotrophin signaling pathway, Hepatitis B, Alzheimer's disease and Oxytocin signaling pathway were significantly changed during aging process in SAMP8 mice. Two key transcription factors of c-Fos and C/EBPbeta were predicted by constructing a TF-target gene network.
CONCLUSION
These putative genes and pathways are closely related to brain senescence and our results would gain new insight into the pathogenesis of brain aging.
背景
衰老是一个复杂的过程，伴随着不同生理功能的下降。在衰老加速模型小鼠 P8（SAMP8）的衰老大脑中已经发现了许多差异表达基因（DEGs），然而，筛选出关键基因是具有挑战性的。
目的
本研究旨在探索 SAMP8 小鼠衰老大脑中的关键基因和途径，这将有助于理解大脑衰老的发病机制。
方法
首先，从 9 项基因表达研究中获得了 430 个在 SAMP8 小鼠与 SAMR1 小鼠之间差异表达的基因，并构建了基因-基因网络。通过聚类分析和拓扑分析，从该网络中筛选出枢纽基因。其次，利用通路富集分析从 430 个 DEGs 中确定关键通路，并将关键通路上的 DEGs 视为功能基因。然后，构建枢纽基因与功能基因之间的内网络，并预测关键基因。部分关键基因通过实时定量 PCR（qRT-PCR）进行了实验验证，并预测了相关的转录因子（TFs）。
结果
我们的结果表明，12 个关键基因可能影响大脑衰老，包括 Trp53、Bcl2、Tnf、Casp9、Fos、Il6、Ptgs2、Il1b、Bdnf、Cdkn1a、Pik3c3 和 Rps6ka1，其中 Casp9、Fos、Ptgs2、Cdkn1a、Pik3c3 和 Rps6ka1 已在 10 月龄 SAMP8 小鼠中通过 qRT-PCR 得到验证。在 SAMP8 小鼠衰老过程中，有 5 个功能组发生了显著变化，包括丝裂原激活蛋白激酶（MAPK）信号通路、神经营养因子信号通路、乙型肝炎、阿尔茨海默病和催产素信号通路。通过构建 TF-靶基因网络，预测到两个关键转录因子 c-Fos 和 C/EBPbeta。
结论
这些候选基因和途径与大脑衰老密切相关，我们的研究结果将为大脑衰老的发病机制提供新的见解。
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