Taylor Jackson, Reynolds Lindsay, Hou Li, Lohman Kurt, Cui Wei, Kritchevsky Stephen, McCall Charles, Liu Yongmei
Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA.
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA.
Immun Ageing. 2017 Jun 20;14:15. doi: 10.1186/s12979-017-0092-5. eCollection 2017.
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 (CD44) and memory (CD44) 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.
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 and , and down-regulation of in both mouse and human CD4+ T cells.
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.
CD4+ T细胞可大致分为初始型和记忆型亚群，每个亚群在衰老过程中受到的损害各不相同。目前尚不清楚这些差异是否以及如何在转录组水平上得到体现。我们对来自年轻（2 - 3个月）和年老（28个月）小鼠的初始型（CD44low）和记忆型（CD44high）CD4+ T细胞的RNA进行了微阵列分析，以便更好地了解这两个亚群中与年龄相关的功能改变机制。我们还进行了后续的生物信息学分析，以确定这两个亚群中基因表达变化的功能后果，并识别可能导致这些变化的调控因子。
我们发现分别有185个和328个基因在年轻与年老的初始型和记忆型细胞中差异表达（FDR≤0.05），其中有50个基因在两个亚群中均差异表达。功能注释分析突出显示了与衰老初始型细胞特异性凋亡相关的基因增加。两个亚群都存在与年龄相关的炎症信号基因增加，以及氧化磷酸化基因减少。顺式调控分析揭示了在与年龄相关表达的基因附近多个转录因子结合位点的富集，特别是NF-κB和几个叉头框转录因子。增强子相关的组蛋白修饰在初始型细胞中下调的基因附近富集。将我们的结果与先前的小鼠和人类数据集进行比较表明，总体上重叠的基因很少，但提示在小鼠和人类CD4+ T细胞中，某些基因一致上调，某些基因一致下调。
初始型和记忆型CD4+ T细胞的转录组受到衰老过程的显著影响。然而，两个亚群都表现出炎症基因普遍增加和氧化磷酸化基因减少。NF-κB、叉头框和Myc转录因子被认为是这两个亚群中这些基因表达变化的上游调节因子，增强子组蛋白修饰可能驱动初始型细胞特有的独特变化。最后我们得出结论，人类和小鼠之间与年龄相关的基因表达变化几乎没有重叠；然而，一小部分基因的与年龄相关的改变可能是保守的。
