Aging increases cell-to-cell transcriptional variability upon immune stimulation
American Association for the Advancement of Science
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Martinez-Jimenez, C., Eling, N., Chen, H., Vallejos, C., Kolodziejczyk, A., Connor, F., Stojic, L., et al. (2017). Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science, 355 (6332), 1433-1436. https://doi.org/10.1126/science.aah4115
Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4(+) T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.
Funded by the European Research Council (F.C., T.F.R., D.T.O., S.A.T., and M.J.T.S.), EMBO Young Investigators Programme (D.T.O.), Cancer Research UK (H.-C.C., M.d.l.R., D.T.O., and J.C.M.), Janet Thornton Fellowship (WT098051 to C.P.M.-J.), Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (107609/Z/15/Z to M.d.l.R.), European Molecular Biology Laboratory (N.E., A.A.K., M.J.T.S., S.A.T., and J.C.M.), Medical Research Council Biostatistics Unit (MRC_MC_UP_0801/1 to C.A.V.), WTSI (C.P.M.-J., S.A.T., J.C.M., and D.T.O.), and Biotechnology and Biological Sciences Research Council–Collaborative Awards in Science and Engineering Studentship with Abcam plc (A.A.K.).
European Research Council (615584)
Cancer Research UK (C14303_do not transfer)
WELLCOME TRUST (107609/Z/15/Z)
Cancer Research UK (unknown)
Cancer Research UK (20412)
Wellcome Trust (202878/Z/16/Z)
External DOI: https://doi.org/10.1126/science.aah4115
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264279