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

Elife. 2021 Mar 16:10:e62250. doi: 10.7554/eLife.62250.

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.

Keywords: D. melanogaster; Polycomb; aging; chromatin; genetics; genomics; intestinal stem cell; lineage fidelity; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / metabolism*
  • Aging / genetics
  • Animals
  • Cell Differentiation / genetics
  • Cell Lineage / genetics*
  • Chromatin / genetics
  • Chromatin / metabolism
  • Drosophila / genetics
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Enterocytes / metabolism
  • Enteroendocrine Cells / metabolism
  • Gene Expression Regulation
  • Homeostasis
  • Intestinal Mucosa / metabolism
  • Intestines / cytology*
  • Polycomb-Group Proteins / genetics*
  • Polycomb-Group Proteins / metabolism
  • Transcriptome

Substances

  • Chromatin
  • Drosophila Proteins
  • Polycomb-Group Proteins

Associated data

  • GEO/GSE164317
  • GEO/GSE157796