Cologne Excellence Cluster on Cellular Stress Responses in Age-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Nat Aging. 2024 Oct;4(10):1432-1445. doi: 10.1038/s43587-024-00696-y. Epub 2024 Sep 3.
Age-related loss of gene expression coordination has been reported for distinct cell types and may lead to impaired cellular function. Here we propose a method for quantifying age-related changes in transcriptional regulatory relationships between genes, based on a model learned from external data. We used this method to uncover age-related trends in gene-gene relationships across eight human tissues, which demonstrates that reduced co-expression may also result from coordinated transcriptional responses. Our analyses reveal similar numbers of strengthening and weakening gene-gene relationships with age, impacting both tissue-specific (for example, coagulation in blood) and ubiquitous biological functions. Regulatory relationships becoming weaker with age were established mostly between genes operating in distinct cellular processes. As opposed to that, regulatory relationships becoming stronger with age were established both within and between different cellular functions. Our work reveals that, although most transcriptional regulatory gene-gene relationships are maintained during aging, those with declining regulatory coupling result mostly from a loss of coordination between distinct cellular processes.
已有研究报道，不同细胞类型的基因表达协调性会随着年龄的增长而下降，这可能导致细胞功能受损。在这里，我们提出了一种基于从外部数据中学习到的模型来量化基因间转录调控关系随年龄变化的方法。我们使用该方法揭示了八个人类组织中基因-基因关系随年龄变化的趋势，这表明共表达的减少也可能是由于转录响应的协调。我们的分析表明，随着年龄的增长，基因-基因关系的增强和减弱趋势相似，影响组织特异性（例如血液中的凝血）和普遍的生物学功能。随着年龄的增长而减弱的调控关系主要是在不同细胞过程中发挥作用的基因之间建立的。相反，随着年龄的增长而增强的调控关系则是在不同的细胞功能内部和之间建立的。我们的工作表明，尽管大多数转录调控基因-基因关系在衰老过程中得以维持，但那些与调控偶联下降相关的关系主要是由于不同细胞过程之间的协调丧失所致。
