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

Autor:	Tauc HM; Immunology Discovery, Genentech, South San Francisco, United States., Rodriguez-Fernandez IA; Immunology Discovery, Genentech, South San Francisco, United States., Hackney JA; OMNI Bioinformatics, Genentech, South San Francisco, United States., Pawlak M; Institute of Hematology and Blood Transfusion, Warsaw, Poland., Ronnen Oron T; Buck Institute for Research on Aging, Novato, United States., Korzelius J; School of Biosciences, University of Kent, Canterbury, United Kingdom., Moussa HF; Department of Biomedical Engineering and Biological Design Center,Boston University, Boston, United States., Chaudhuri S; Department of Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing, Genentech, South San Francisco, United States., Modrusan Z; Immunology Discovery, Genentech, South San Francisco, United States.; Department of Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing, Genentech, South San Francisco, United States., Edgar BA; Huntsman Cancer Institute, University of Utah, Salt Lake City, United States., Jasper H; Immunology Discovery, Genentech, South San Francisco, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Mar 16; Vol. 10. Date of Electronic Publication: 2021 Mar 16.
DOI:	10.7554/eLife.62250
Abstrakt:	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. Competing Interests: HT, IR, JH, SC, ZM employee of Genentech Inc, MP, TR, JK, HM, BE, HJ No competing interests declared (© 2021, Tauc et al.)
Databáze:	MEDLINE
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