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

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.

An amuse-bouche of stem cell regulation: Underlying principles and mechanisms from adult Drosophila intestinal stem cells

“…Single-cell RNA-seq data has provided additional evidence that EE cells originate through distinct EEPs [11,30]. It was recently suggested that EE priming in progenitor cells is epigenetically regulated by Polycomb complex proteins [31]. The inactivation of Polycomb leads to downregulation of EE genes, which is likely indirect given Polycomb's well-characterized role in transcriptional repression.…”

“…Recent ATAC-seq data suggests that aging leads to mild alteration of chromatin accessibility at promoters enriched for binding motifs of Polycomb interactors. The authors suggest that changes in ISC H3K27me2 levels, catalyzed by the Polycomb Repressive Complex 2 (PRC2), lead to a bias toward EE fate by upregulation of EE-specific gene expression [31]. Further characterization of chromatin states in young and aged stem cells would be required to establish the full extent of epigenetic alterations in ISC and differentiated cells.…”

Decoding Aging Hallmarks at the Single-Cell Level

“…Among the cell types in the intestine, an age-related decline in the regenerative capability of intestinal stem cells (ISCs), which regenerate the gastrointestinal epithelium, significantly perturbs intestinal homeostasis (133). Using the Drosophila intestine as a model to explore stem cell-intrinsic changes during aging, Tauc et al (134) employed bulk genome-wide chromatin accessibility and transcriptome analysis combined with scRNA-seq to find that promoters of Polycomb target genes become differentially accessible in aged ISCs, resulting in increased expression of enteroendocrine cell specification genes and biased differentiation. In a related study, which reported the construction of an enteric neuronal atlas using RAISIN (ribosomes and intact single nucleus) RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq (mining rare cells sequencing) for label-free enrichment of rare cell types by droplet-based profiling, dysregulation of circadian genes and genes involved in age-related CNS diseases segregated with chronological age in enteric neurons, suggesting its tight correlation with intestinal and extraintestinal diseases (135).…”

ImAge: an imaging approach to quantitate aging and rejuvenation

“…Although we documented this effect for CD3+ and CD3-cells in the blood and between 5 different organs, this is likely a general phenomenon. This could be explained by the age-related erosion of epigenetic and chromatin landscape 39 which increases the noise in part through cell-to-cell variation in gene expression 95 , loss of lineage fidelity with age, and activation of lineage-inappropriate genes during aging 81,[96][97][98][99] . Reactivation of human endogenous retroviruses during aging could also contribute to this process 100,101 .…”