BACKGROUND CD4+ T cells can be broadly divided into naïve and memory subsets, each of which are differentially impaired by the aging process. It is unclear if and how these differences are reflected at the transcriptomic level. We performed microarray profiling on RNA derived from naïve (CD44low) and memory (CD44high) CD4+ T cells derived from young (2-3 month) and old (28 month) mice, in order to better understand the mechanisms of age-related functional alterations in both subsets. We also performed follow-up bioinformatic analyses in order to determine the functional consequences of gene expression changes in both of these subsets, and identify regulatory factors potentially responsible for these changes. RESULTS We found 185 and 328 genes differentially expressed (FDR ≤ 0.05) in young vs. old naïve and memory cells, respectively, with 50 genes differentially expressed in both subsets. Functional annotation analyses highlighted an increase in genes involved in apoptosis specific to aged naïve cells. Both subsets shared age-related increases in inflammatory signaling genes, along with a decrease in oxidative phosphorylation genes. Cis-regulatory analyses revealed enrichment of multiple transcription factor binding sites near genes with age-associated expression, in particular NF-κB and several forkhead box transcription factors. Enhancer associated histone modifications were enriched near genes down-regulated in naïve cells. Comparison of our results with previous mouse and human datasets indicates few overlapping genes overall, but suggest consistent up-regulation of Casp1 and Il1r2, and down-regulation of Foxp1 in both mouse and human CD4+ T cells. CONCLUSIONS The transcriptomes of naïve and memory CD4+ T cells are distinctly affected by the aging process. However, both subsets exhibit a common increase inflammatory genes and decrease in oxidative phosphorylation genes. NF-κB, forkhead box, and Myc transcription factors are implicated as upstream regulators of these gene expression changes in both subsets, with enhancer histone modifications potentially driving unique changes unique to naïve cells. Finally we conclude that there is little overlap in age-related gene expression changes between humans and mice; however, age-related alterations in a small subset of genes may be conserved.

中文翻译：

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小鼠幼稚和记忆CD4 +细胞衰老的转录组学概况。

背景技术CD4 + T细胞可大致分为幼稚和记忆子集，每个子​​集都会因衰老过程而受到不同程度的损害。尚不清楚这些差异是否以及如何在转录组水平上反映出来。为了更好地了解与年龄相关的功能改变的机制，我们对源自幼稚（2-3个月）和老年（28个月）小鼠的幼稚（CD44low）和记忆（CD44high）CD4 + T细胞的RNA进行了微阵列分析在两个子集中。我们还进行了后续的生物信息学分析，以确定这两个亚组中基因表达变化的功能后果，并确定可能导致这些变化的调节因子。结果我们发现在幼稚和老年幼稚和记忆细胞中分别有185和328个基因差异表达（FDR≤0.05），两个子集中有50个差异表达的基因。功能注释分析突出显示了与老化的幼稚细胞特异的凋亡相关基因的增加。这两个子集都与年龄相关的炎症信号基因增加，同时氧化磷酸化基因减少。顺式调节分析显示，与年龄相关的表达，尤其是NF-κB和几个叉头盒转录因子的基因附近的多个转录因子结合位点的富集。与增强子相关的组蛋白修饰富集在幼稚细胞中下调的基因附近。我们的结果与以前的小鼠和人类数据集的比较表明总体上几乎没有重叠的基因，但是表明小鼠和人类CD4 + T细胞中Casp1和Il1r2的一致上调以及Foxp1的下调。结论幼稚和记忆CD4 + T细胞的转录组明显受到衰老过程的影响。但是，这两个子集都显示出共同增加的炎症基因和氧化磷酸化基因的减少。NF-κB，叉头盒和Myc转录因子与这两个亚组中这些基因表达变化的上游调控因子有关，其中增强子组蛋白修饰可能驱动幼稚细胞特有的独特变化。最后，我们得出结论，人与小鼠之间与年龄相关的基因表达变化几乎没有重叠。但是，可以保留一小部分基因中与年龄相关的改变。叉头盒和Myc转录因子与这两个亚组中这些基因表达变化的上游调节物有关，增强子组蛋白修饰可能驱动幼稚细胞特有的独特变化。最后，我们得出结论，人与小鼠之间与年龄相关的基因表达变化几乎没有重叠。但是，可以保留一小部分基因中与年龄相关的改变。叉头盒和Myc转录因子与这两个亚组中这些基因表达变化的上游调节物有关，增强子组蛋白修饰可能驱动幼稚细胞特有的独特变化。最后，我们得出结论，人与小鼠之间与年龄相关的基因表达变化几乎没有重叠。但是，可以保留一小部分基因中与年龄相关的改变。