Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity

Abstract
Data availability
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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.

The following data sets were generated

1. Izgi H
2. Han D
3. Isildak U
4. Huang S
5. Kocabiyik E
6. Khaitovich P
7. Somel M
8. Donertas HM
(2021) Bulk RNA-seq of mice covering the whole lifespan (2 days to 904 days) from four tissues
NCBI Gene Expression Omnibus, GSE167665.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE167665

The following previously published data sets were used

(2013) Aging Experiment
NCBI Gene Expression Omnibus, GSE34378.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE34378
1. GTEx Consortium et al
(2017) Gene TPMs
GTEx Portal, phs000424.v8.p2.

https://storage.googleapis.com/gtex_analysis_v8/rna_seq_data/GTEx_Analysis_2017-06-05_v8_RNASeQCv1.1.9_gene_tpm.gct.gz
1. Pisco
2. Angela
(2020) Official data release for Tabula Muris Senis
figshare, https://doi.org/10.6084/m9.figshare.12654728.v1.

https://figshare.com/articles/dataset/Tabula_Muris_Senis_Data_Objects/12654728
1. Schaum et al
(2020) Tabula Muris Senis: Bulk sequencing
NCBI Gene Expression Omnibus, GSE132040.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE132040

Article and author information

Author details

Hamit Izgi

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4030-3132
DingDing Han

CAS Key Laboratory of Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Ulas Isildak

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Competing interests
The authors declare that no competing interests exist.
Shuyun Huang

CAS Key Laboratory of Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Ece Kocabiyik

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Competing interests
The authors declare that no competing interests exist.
Philipp Khaitovich

Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, Moscow, Russian Federation

For correspondence
p.khaitovich@skoltech.ru

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4305-0054
Mehmet Somel

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

For correspondence
somel.mehmet@googlemail.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3138-1307
Handan Melike Dönertaş

Leibniz Institute on Aging - Fritz Lipmann Institute, Cambridge, United Kingdom

For correspondence
donertas.melike@gmail.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9788-6535

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

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.