Age-related changes in Polycomb gene regulation disrupt lineage fidelity in intestinal stem cells

  1. Helen M Tauc
  2. Imilce A Rodriguez-Fernandez
  3. Jason A Hackney
  4. Michal Pawlak
  5. Tal Ronnen Oron
  6. Jerome Korzelius
  7. Hagar F Moussa
  8. Subhra Chaudhuri
  9. Zora Modrusan
  10. Bruce A Edgar
  11. Heinrich Jasper  Is a corresponding author
  1. Genentech, Inc, United States
  2. Institute of Hematology and Blood Transfusion, Poland
  3. Buck Institute for Research on Aging, United States
  4. University of Kent, United Kingdom
  5. Vienna BioCenter (VBC), Austria
  6. University of Utah, United States

Abstract

Tissue homeostasis requires long-term lineage fidelity of somatic stem cells. Whether and how age-related changes in somatic stem cells impact the faithful execution of lineage decisions remains largely unknown. Here, we address this question using genome-wide chromatin accessibility and transcriptome analysis as well as single cell RNA-seq to explore stem cell-intrinsic changes in the aging Drosophila intestine. These studies indicate that in stem cells of old flies, promoters of Polycomb (Pc) target genes become differentially accessible, resulting in the increased expression of enteroendocrine (EE) cell specification genes. Consistently, we find age-related changes in the composition of the EE progenitor cell population in aging intestines, as well as a significant increase in the proportion of EE-specified intestinal stem cells (ISCs) and progenitors in aging flies. We further confirm that Pc-mediated chromatin regulation is a critical determinant of EE cell specification in the Drosophila intestine. Pc is required to maintain expression of stem cell genes while ensuring repression of differentiation and specification genes. Our results identify Pc group proteins as central regulators of lineage identity in the intestinal epithelium and highlight the impact of age-related decline in chromatin regulation on tissue homeostasis.

Data availability

Data generated and analysed are included in the manuscript, figures and figure supplements.All sequencing data generated in this study have been deposited in GEO under accession code GSE164317.

Article and author information

Author details

  1. Helen M Tauc

    Immunology Discovery, Genentech, Inc, South San Francisco, United States
    Competing interests
    Helen M Tauc, employee of Genentech Inc.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0694-2387
  2. Imilce A Rodriguez-Fernandez

    Immunology Discovery, Genentech, Inc, South San Francisco, United States
    Competing interests
    Imilce A Rodriguez-Fernandez, employee of Genentech Inc.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5112-4834
  3. Jason A Hackney

    Bioinformatics, Genentech, Inc, South San Francisco, United States
    Competing interests
    Jason A Hackney, employee of Genentech Inc.
  4. Michal Pawlak

    Bioinformatics, Institute of Hematology and Blood Transfusion, Warsaw, Poland
    Competing interests
    No competing interests declared.
  5. Tal Ronnen Oron

    Bioinformatics, Buck Institute for Research on Aging, Novato, United States
    Competing interests
    No competing interests declared.
  6. Jerome Korzelius

    School of Biosciences, University of Kent, Canterbury, United Kingdom
    Competing interests
    No competing interests declared.
  7. Hagar F Moussa

    Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3463-0126
  8. Subhra Chaudhuri

    Micro Array Lab, Genentech, Inc, South San Francisco, United States
    Competing interests
    Subhra Chaudhuri, employee of Genentech Inc.
  9. Zora Modrusan

    Microchemistry, Proteomics and Lipidomics, Genentech, Inc, South San Francisco, United States
    Competing interests
    Zora Modrusan, employee of Genentech Inc.
  10. Bruce A Edgar

    Department of Oncological Sciences, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3383-2044
  11. Heinrich Jasper

    Immunology Discovery, Genentech, Inc, South San Francisco, United States
    For correspondence
    jasper.heinrich@gene.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6014-4343

Funding

EMBO Long-Term Fellowship (ALTF 1516-2011)

  • Jerome Korzelius

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jing-Dong Jackie Han, Chinese Academy of Sciences, China

Version history

  1. Received: August 19, 2020
  2. Accepted: March 15, 2021
  3. Accepted Manuscript published: March 16, 2021 (version 1)
  4. Version of Record published: March 22, 2021 (version 2)

Copyright

© 2021, Tauc 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. Helen M Tauc
  2. Imilce A Rodriguez-Fernandez
  3. Jason A Hackney
  4. Michal Pawlak
  5. Tal Ronnen Oron
  6. Jerome Korzelius
  7. Hagar F Moussa
  8. Subhra Chaudhuri
  9. Zora Modrusan
  10. Bruce A Edgar
  11. Heinrich Jasper
(2021)
Age-related changes in Polycomb gene regulation disrupt lineage fidelity in intestinal stem cells
eLife 10:e62250.
https://doi.org/10.7554/eLife.62250

Share this article

https://doi.org/10.7554/eLife.62250

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