The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis -regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening. [Display omitted] • Multi-omic analysis of maturation and aging across >45 mouse and human cell types • Common transcription factor pattern for chromatin remodeling in maturation and aging • Encoded via relative abundance of AP-1, CTCF, and cell identity factor binding sites • Remodeling mechanism activated by AP-1, stress, systemic factor, or PRC2 inhibition Patrick and Naval-Sanchez et al. offer a mechanistic connection between molecular remodeling in organismal maturation and aging. Through multi-omic analysis of both processes, they reveal a shared transcription factor binding pattern within genomic regulatory elements, underpinned by binding site abundance differences for AP-1, CTCF, and cell identity transcription factors. [ABSTRACT FROM AUTHOR]