Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression.
Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression.
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DOI：
10.1186/s13059-021-02585-8
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发表时间：
2022-01-14
期刊：
影响因子：
12.3
通讯作者：
Heijmans BT
中科院分区：
文献类型：
--
作者：
Jonkman TH;Dekkers KF;Slieker RC;Grant CD;Ikram MA;van Greevenbroek MMJ;Franke L;Veldink JH;Boomsma DI;Slagboom PE;Consortium BIOS;Heijmans BT
表观遗传时钟使用特定CpG二核苷酸组的DNA甲基化（DNAm）水平来准确预测个体的实际年龄。这些时钟的一个流行应用是探索预测年龄与实际年龄的偏差是否与疾病表型相关，其中这种偏差被解释为生物学年龄的潜在生物标志物。然而，这种广泛的应用与对可能驱动表观遗传时钟运行的过程的有限洞察形成了鲜明对比。我们使用来自3132个个体的血液DNA甲基化组和转录组数据对四个表观遗传时钟进行功能基因组学分析，包括Hannum的血液预测器和Horvath的多组织预测器。四个时钟导致个体实足年龄的相似预测，并且它们的构成CpG在DNAm水平上相关，并且富集相似的组蛋白修饰和染色质状态。有趣的是，时钟中CpG的DNAm水平通常与反式基因表达相关。所涉及的基因组高度重叠，并富集T细胞过程。对分选的血细胞类型的转录组和甲基化组的进一步分析鉴定了初始和活化的T细胞和NK细胞之间的DNAm的差异作为时钟的可能贡献者。事实上，在同一供体中，四个表观遗传时钟预测幼稚细胞比活化细胞年轻40岁。表观遗传时钟预测实足年龄的能力涉及它们检测幼稚和活化免疫血细胞比例变化的能力，这是免疫衰老的一个既定特征。这一发现可能有助于解释时钟衍生的措施和年龄相关的健康结果之间的关联。在线版本包含补充材料，可通过10.1186/s13059-021-02585-8获取。
Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks. We perform a functional genomics analysis on four epigenetic clocks, including Hannum’s blood predictor and Horvath’s multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells. The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes. The online version contains supplementary material available at 10.1186/s13059-021-02585-8.
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影响因子：
13.8
作者：
Gates LA;Foulds CE;O'Malley BW
通讯作者：
O'Malley BW
影响因子：
3.7
作者：
Bocklandt S;Lin W;Sehl ME;Sánchez FJ;Sinsheimer JS;Horvath S;Vilain E
通讯作者：
Vilain E
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
3.9
作者：
Kananen, Laura;Nevalainen, Tapio;Hurme, Mikko
通讯作者：
Hurme, Mikko
影响因子：
13.6
作者：
Hofman A;Brusselle GG;Darwish Murad S;van Duijn CM;Franco OH;Goedegebure A;Ikram MA;Klaver CC;Nijsten TE;Peeters RP;Stricker BH;Tiemeier HW;Uitterlinden AG;Vernooij MW
通讯作者：
Vernooij MW