Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity
- Middle East Technical University, Turkey
- Shanghai Institutes for Biological Sciences, China
- Skolkovo Institute of Science and Technology, Russian Federation
- Leibniz Institute on Aging - Fritz Lipmann Institute, Germany
Abstract
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.
Data availability
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.
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Bulk RNA-seq of mice covering the whole lifespan (2 days to 904 days) from four tissuesNCBI Gene Expression Omnibus, GSE167665.
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Aging ExperimentNCBI Gene Expression Omnibus, GSE34378.
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Official data release for Tabula Muris Senisfigshare, https://doi.org/10.6084/m9.figshare.12654728.v1.
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Tabula Muris Senis: Bulk sequencingNCBI Gene Expression Omnibus, GSE132040.
Article and author information
Author details
Philipp Khaitovich
Handan Melike Dönertaş
Funding
European Molecular Biology Laboratory
- Handan Melike Dönertaş
Scientific and Technological Council of Turkey (2232)
- Mehmet Somel
Science Academy BAGEP Awards
- Mehmet Somel
METU Internal Grant
- Mehmet Somel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
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.
Copyright
© 2022, Izgi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity
eLife 11:e68048.
https://doi.org/10.7554/eLife.68048
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Enhancers and promoters are classically considered to be bound by a small set of transcription factors (TFs) in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract hundreds of TFs with often no detectable correlation between ChIP-seq peaks and DNA-binding motif presence. Here, we used a set of 1003 TF ChIP-seq datasets (HepG2, K562, H1) to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We identified 43,891 HOT loci forming at the promoter (53%) and enhancer (47%) regions. HOT promoters regulate housekeeping genes, whereas HOT enhancers are involved in tissue-specific process regulation. HOT loci form the foundation of human super-enhancers and evolve under strong negative selection, with some of these loci being located in ultraconserved regions. Sequence-based classification analysis of HOT loci suggested that their formation is driven by the sequence features, and the density of mapped ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. Based on the affinities to bind to promoters and enhancers we detected five distinct clusters of TFs that form the core of the HOT loci. We report an abundance of HOT loci in the human genome and a commitment of 51% of all TF ChIP-seq binding events to HOT locus formation thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.
