Department of Physics, Bar-Ilan University, Ramat-Gan, Israel.
The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat-Gan, Israel.
Nat Metab. 2020 Nov;2(11):1305-1315. doi: 10.1038/s42255-020-00304-4. Epub 2020 Nov 2.
A long-standing model holds that stochastic aberrations of transcriptional regulation play a key role in the process of ageing. While transcriptional dysregulation is observed in many cell types in the form of increased cell-to-cell variability, its generality to all cell types remains doubted. Here, we propose a new approach for analysing transcriptional regulation in single-cell RNA sequencing data by focusing on the global coordination between the genes rather than the variability of individual genes or correlations between pairs of genes. Consistently, across very different organisms and cell types, we find a decrease in the gene-to-gene transcriptional coordination in ageing cells. In addition, we find that loss of gene-to-gene transcriptional coordination is associated with high mutational load of a specific, age-related signature and with radiation-induced DNA damage. These observations suggest a general, potentially universal, stochastic attribute of transcriptional dysregulation in ageing.
长期以来，有一种观点认为转录调控的随机波动在衰老过程中起着关键作用。虽然在许多细胞类型中都观察到转录失调，表现为细胞间变异性增加，但这种失调是否普遍存在于所有细胞类型仍存在疑问。在这里，我们提出了一种新的方法，通过关注基因之间的全局协调，而不是单个基因的变异性或基因对之间的相关性，来分析单细胞 RNA 测序数据中的转录调控。一致的是，在非常不同的生物体和细胞类型中，我们发现衰老细胞中的基因间转录协调减少。此外，我们发现基因间转录协调的丧失与特定的、与年龄相关的特征的高突变负荷以及辐射诱导的 DNA 损伤有关。这些观察结果表明，转录失调在衰老过程中具有普遍的、潜在的随机属性。
