Age-related changes in Polycomb gene regulation disrupt lineage fidelity in intestinal stem cells
- Genentech, Inc, United States
- Institute of Hematology and Blood Transfusion, Poland
- Buck Institute for Research on Aging, United States
- University of Kent, United Kingdom
- Vienna BioCenter (VBC), Austria
- 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
Imilce A Rodriguez-Fernandez
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
- Jing-Dong Jackie Han, Chinese Academy of Sciences, China
Version history
- Received: August 19, 2020
- Accepted: March 15, 2021
- Accepted Manuscript published: March 16, 2021 (version 1)
- 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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Age-related changes in Polycomb gene regulation disrupt lineage fidelity in intestinal stem cells
eLife 10:e62250.
https://doi.org/10.7554/eLife.62250
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