Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term Divergence followed by Convergence, or DiCo. We found that DiCo was most prevalent among tissue-specific genes and associated with loss of tissue identity, which is confirmed using data from independent mouse and human datasets. Further, using publicly available single-cell transcriptome data, we showed that DiCo could be driven both by alterations in tissue cell type composition and also by cell-autonomous expression changes within particular cell types.
Sequencing data generated for this study have been deposited in GEO under accession code GSE167665. All data analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and figure supplements.Four additional and previously published datasets are used in this study:Jonker et al. 2013, GTEx Consortium et al. 2017, Schaum et al. 2020, and Tabula Muris Consortium 2020.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Post-mortem samples were obtained from 16 C57BL/6J mice aged between 2 days and 904 days. All mouse experiments were overseen by the Institutional Animal Welfare Officer of the Max Planck Institute for Evolutionary Anthropology (MPI-EVA). They were performed according to the German Animal Welfare Legislation, ("Tierschutzgesetz") and registered with the Federal State Authority Landesdirektion Sachsen (No. 24-9162. 11-01 (T62/08)). The mice were sacrificed for reasons independent of this study, their tissues were harvested and frozen immediately, and stored at -80{degree sign}C.
Human subjects: Data involving human subjects were obtained from a published dataset, GTEx portal (https://www.gtexportal.org/home/datasets, with accession phs000424.v8.p2). Hence, no ethical statement is required.
© 2022, Izgi et al.
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Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
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