Polycomb-dependent breakdown of the intestinal barrier in aging Drosophila

Aging compromises gut integrity, yet the chromatin changes driving this decline remain unclear. Polycomb mediated repression is essential for developmental silencing, but becomes dysregulated with age. Using single-cell chromatin profiling of the Drosophila intestine, we find that intestinal cell types have distinct repressed landscapes, and that enterocytes — not stem cells — undergo the most significant chromatin shifts in older animals. Aged enterocytes aberrantly repress genes essential for transmembrane transport and chitin metabolism, contributing to gut barrier decline. In contrast, stem cells exhibit increased proliferation, linked to hypertranscription of S-phase histone genes and to activation of JAK-STAT signalling pathways. These findings suggest that aberrant Polycomb repression in old differentiated cells is an example of antagonistic pleiotropy aging animals. Overall design: We used Cleavage under targets and Tagmentation (Cut-and-Tag), a chromatin profiling strategy in which antibody-targeted controlled integration of DNA sequencing adapters produces libraries for paired-end DNA sequencing.