Global mapping of transcription factor motifs in human aging.
Global mapping of transcription factor motifs in human aging.
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DOI：
10.1371/journal.pone.0190457
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Kriete A
中科院分区：
文献类型：
--
作者：
Alfego D;Rodeck U;Kriete A
生物衰老是一个复杂的过程，依赖于细胞自主和组织环境变化的相互作用，这些变化是响应累积分子应激而发生的，并通过适应性转录重编程表现出来。在这里，我们描述了对基因表达数据集的转录因子（TF）荟萃分析，这些数据集是从不同生物年龄和 7 个不同的体外衰老模型收集的 18 个组织位点中收集的。体外衰老平台包括复制衰老和静止能量限制模型（ERiQ），其中 ATP 瞬时减少。使用 JASPAR 和 TRANSFAC 扫描修剪后的靶基因组启动子区域中的 TF 基序。当按层次排列时，TF 签名建立了具有不同簇的聚集基序的全局映射。值得注意的是，ERiQ 谱与大多数体内老化组织相同。在简约的蛋白质-蛋白质网络中安装基序可以探测与不同压力传感器的连接性。 DNA 损伤传感器 ATM 和 ATR 与衰老相关的子网络相连。相比之下，能量传感器 PTEN 和 AMPK 连接到 ERiQ 子网络中的节点。这些数据表明，代谢功能障碍可能与许多衰老组织特有的转录模式有关，并且与衰老相关的累积 DNA 损伤不同。
Biological aging is a complex process dependent on the interplay of cell autonomous and tissue contextual changes which occur in response to cumulative molecular stress and manifest through adaptive transcriptional reprogramming. Here we describe a transcription factor (TF) meta-analysis of gene expression datasets accrued from 18 tissue sites collected at different biological ages and from 7 different in-vitro aging models. In-vitro aging platforms included replicative senescence and an energy restriction model in quiescence (ERiQ), in which ATP was transiently reduced. TF motifs in promoter regions of trimmed sets of target genes were scanned using JASPAR and TRANSFAC. TF signatures established a global mapping of agglomerating motifs with distinct clusters when ranked hierarchically. Remarkably, the ERiQ profile was shared with the majority of in-vivo aged tissues. Fitting motifs in a minimalistic protein-protein network allowed to probe for connectivity to distinct stress sensors. The DNA damage sensors ATM and ATR linked to the subnetwork associated with senescence. By contrast, the energy sensors PTEN and AMPK connected to the nodes in the ERiQ subnetwork. These data suggest that metabolic dysfunction may be linked to transcriptional patterns characteristic of many aged tissues and distinct from cumulative DNA damage associated with senescence.