He Kan, Zhou Tao, Shao Jiaofang, Ren Xiaoliang, Zhao Zhongying, Liu Dahai
Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei City, Anhui, P. R. China, 230601.
Aging (Albany NY). 2014 Mar;6(3):215-30. doi: 10.18632/aging.100648.
Numerous genetic targets and some individual pathways associated with aging have been identified using the worm model. However, less is known about the genetic mechanisms of aging in genome wide, particularly at the level of multiple pathways as well as the regulatory networks during aging. Here, we employed the gene expression datasets of three time points during aging in Caenorhabditis elegans (C. elegans) and performed the approach of gene set enrichment analysis (GSEA) on each dataset between adjacent stages. As a result, multiple genetic pathways and targets were identified as significantly down- or up-regulated. Among them, 5 truly aging-dependent signaling pathways including MAPK signaling pathway, mTOR signaling pathway, Wnt signaling pathway, TGF-beta signaling pathway and ErbB signaling pathway as well as 12 significantly associated genes were identified with dynamic expression pattern during aging. On the other hand, the continued declines in the regulation of several metabolic pathways have been demonstrated to display age-related changes. Furthermore, the reconstructed regulatory networks based on three of aging related Chromatin immunoprecipitation experiments followed by sequencing (ChIP-seq) datasets and the expression matrices of 154 involved genes in above signaling pathways provide new insights into aging at the multiple pathways level. The combination of multiple genetic pathways and targets needs to be taken into consideration in future studies of aging, in which the dynamic regulation would be uncovered.
利用线虫模型已经鉴定出许多与衰老相关的基因靶点和一些个体通路。然而，在全基因组范围内，人们对衰老的遗传机制了解较少，尤其是在衰老过程中多个通路以及调控网络层面。在此，我们利用秀丽隐杆线虫（C. elegans）衰老过程中三个时间点的基因表达数据集，并对相邻阶段的每个数据集进行基因集富集分析（GSEA）。结果，鉴定出多个基因通路和靶点显著下调或上调。其中，鉴定出5条真正依赖衰老的信号通路，包括丝裂原活化蛋白激酶（MAPK）信号通路、雷帕霉素靶蛋白（mTOR）信号通路、Wnt信号通路、转化生长因子-β（TGF-β）信号通路和表皮生长因子受体（ErbB）信号通路，以及12个在衰老过程中具有动态表达模式的显著相关基因。另一方面，已证明几种代谢通路调控的持续下降呈现出与年龄相关的变化。此外，基于三个衰老相关的染色质免疫沉淀测序（ChIP-seq）数据集以及上述信号通路中154个相关基因的表达矩阵重建的调控网络，为多通路水平的衰老研究提供了新的见解。在未来衰老研究中，需要考虑多个基因通路和靶点的组合，其中将揭示动态调控机制。
