Polycomb misregulation in enterocytes drives tissue decline in the aging Drosophila intestine

Aging compromises intestinal integrity, yet the chromatin changes driving this decline remain unclear. Polycomb-mediated repression is essential for silencing developmental genes, but this regulatory mechanism becomes dysregulated with age. Although shifts in Polycomb regulation within intestinal stem cells have been linked to gut aging, the Polycomb landscape of differentiated cell types remains unexplored. Differentiated cells comprise the majority of the gut epithelium and directly impact both tissue and whole organismal aging. Using single-cell chromatin profiling of the Drosophila intestine, we identify cell type–specific chromatin landscape changes during aging. We find that old enterocytes aberrantly repress genes essential for transmembrane transport and chitin metabolism, contributing to intestinal barrier decline, an example of antagonistic pleiotropy in a regenerative tissue. Barrier decline leads to derepression of JAK/STAT ligands in all cell types and increased proliferation of aging stem cells, with elevated RNA polymerase II (RNAPII) at S-phase-dependent histone genes. Specific upregulation of histone genes during aging stem cell proliferation resembles RNAPII hypertranscription of histone genes in aggressive human cancers. Our work reveals that misregulation of the Polycomb-mediated H3K27me3 histone modification in differentiated cells during aging not only underlies tissue decline but also mirrors transcriptional changes in cancer, suggesting a common mechanism linking aging and cancer progression.