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

  1. Hamit Izgi
  2. DingDing Han
  3. Ulas Isildak
  4. Shuyun Huang
  5. Ece Kocabiyik
  6. Philipp Khaitovich  Is a corresponding author
  7. Mehmet Somel  Is a corresponding author
  8. Handan Melike Dönertaş  Is a corresponding author
  1. Middle East Technical University, Turkey
  2. Shanghai Institutes for Biological Sciences, China
  3. Skolkovo Institute of Science and Technology, Russian Federation
  4. 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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Hamit Izgi

    Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4030-3132
  2. 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.
  3. Ulas Isildak

    Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
  5. Ece Kocabiyik

    Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4305-0054
  7. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3138-1307
  8. Handan Melike Dönertaş

    Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
    For correspondence
    donertas.melike@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "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.

Reviewing Editor

  1. Bérénice A Benayoun, University of Southern California, United States

Publication history

  1. Preprint posted: March 2, 2021 (view preprint)
  2. Received: March 3, 2021
  3. Accepted: January 28, 2022
  4. Accepted Manuscript published: January 31, 2022 (version 1)
  5. Accepted Manuscript updated: February 1, 2022 (version 2)
  6. Version of Record published: February 25, 2022 (version 3)
  7. Version of Record updated: March 3, 2022 (version 4)

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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  1. Hamit Izgi
  2. DingDing Han
  3. Ulas Isildak
  4. Shuyun Huang
  5. Ece Kocabiyik
  6. Philipp Khaitovich
  7. Mehmet Somel
  8. Handan Melike Dönertaş
(2022)
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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