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, United Kingdom
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
Further reading
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- Epidemiology and Global Health
- Genetics and Genomics
Background:
Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations.
Methods:
We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504).
Results:
Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (–0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (–0.043±0.013 kg, p=0.0011) in the combined cohorts.
Conclusions:
This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers.
Funding:
This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.
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- Cancer Biology
- Genetics and Genomics
It takes more than 20 years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here, we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into six modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.
