Abstract
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.
Original language | English |
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Pages (from-to) | 1305-1315 |
Number of pages | 11 |
Journal | Nature Metabolism |
Volume | 2 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2020 |
Bibliographical note
Publisher Copyright:© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Funding
We thank M. Enge for sharing experimental data and for his helpful support. We also thank M.L. Rizzo, E. Eisenberg, Y. Brody, R. Cohen and S. Havlin for helpful discussions. Y.-Y.L. acknowledged grants from National Institutes of Health (R01AI141529, R01HD093761, UH3OD023268, U19AI095219 and U01HL089856). The project described was supported in part by award numbers R01 HL124233 and R01 HL147326 from the National Heart, Lung, and Blood Institute and the FDA Center for Tobacco Products (CTP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. A.B. thanks the Azrieli Foundation for supporting this research.
Funders | Funder number |
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National Institutes of Health | U19AI095219, R01 HL147326, UH3OD023268, R01HD093761, R01AI141529 |
National Heart, Lung, and Blood Institute | R01HL124233, U01HL089856 |
Food and Drug Administration | |
Azrieli Foundation |