Longitudinal epigenetic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes involved in protein translation in human aging.
Longitudinal epigenetic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes involved in protein translation in human aging.
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DOI：
10.1093/nar/gkv473
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发表时间：
2015-09-03
影响因子：
14.9
通讯作者：
Pfeifer GP
中科院分区：
文献类型：
--
作者：
Jung M;Jin SG;Zhang X;Xiong W;Gogoshin G;Rodin AS;Pfeifer GP
关于衰老的生物学机制的数据大多来自横截面研究设计。这种设计的一个固有缺点是，个体间的差异可能会掩盖微小但具有生物学意义的年龄依赖性变化。连续采样设计（同一个体在不同时间点）可以克服这个问题，但通常受到可用配对样本数量相对较少和所使用统计量的限制。为了克服这些局限性，我们开发了一种新的基于向量的方法，称为三组分分析，它将时间距离，信号强度和方差纳入一个单一的基因排名得分，并结合基因集富集分析。我们在一个独特的基于年龄的人类皮肤成纤维细胞样本集上测试了我们的方法，并结合了全基因组转录，DNA甲基化和组蛋白甲基化（H3K4me3和H3K27me3）数据。重要的是，我们的方法现在可以第一次证明编码参与翻译和核糖体功能的蛋白质的基因表达的明显年龄依赖性降低。利用来自低等生物的数据进行类比，我们提出了一个模型，其中蛋白质分解相关组分的年龄依赖性下调有助于延长人类寿命。
Data on biological mechanisms of aging are mostly obtained from cross-sectional study designs. An inherent disadvantage of this design is that inter-individual differences can mask small but biologically significant age-dependent changes. A serially sampled design (same individual at different time points) would overcome this problem but is often limited by the relatively small numbers of available paired samples and the statistics being used. To overcome these limitations, we have developed a new vector-based approach, termed three-component analysis, which incorporates temporal distance, signal intensity and variance into one single score for gene ranking and is combined with gene set enrichment analysis. We tested our method on a unique age-based sample set of human skin fibroblasts and combined genome-wide transcription, DNA methylation and histone methylation (H3K4me3 and H3K27me3) data. Importantly, our method can now for the first time demonstrate a clear age-dependent decrease in expression of genes coding for proteins involved in translation and ribosome function. Using analogies with data from lower organisms, we propose a model where age-dependent down-regulation of protein translation-related components contributes to extend human lifespan.