In this world nothing can be said to be certain, except Spain winning at football and age-related chromatin remodeling! While this remodeling was thought to drive aging via the loss of epigenetic information, new research provides evidence for the “hijacking” of developmental maturation via activator protein 1 (AP-1)-activity as a major player.
Surefire researchers “captained” by Christian M. Nefzger (University of Queensland) hypothesized that epigenetics could mechanistically connect developmental maturation and aging. Therefore, the team profiled age-related alterations to chromatin remodeling and gene expression in murine cells from 11 tissues by multiomic bulk profiling (OMNI-ATAC-seq and RNA-seq) and analyzed previously reported cell maturation/aging datasets for mouse (and human) cells. Their analyses suggested that AP-1-linked chromatin opening at candidate cis-regulatory elements (cCREs) and transcription factor (TF) redistribution during developmental maturation becomes “hijacked” over time to induce aging phenotypes.
Let’s hear more from Patrick, Naval-Sanchez, and Colleagues on the hijacking of developmental maturation during aging:
- High-resolution analysis of age-related chromatin remodeling and TF redistribution uncovers a TF binding site (TFBS) signature common to developmental maturation and aging characterized by the differential presence of cell-identity/AP-1 TFBSs at cCREs
- Early-life cCREs losing accessibility during maturation/aging display enriched cell-identity TFBSs and low AP-1 binding
- AP-1 binding with cell-identity TFs at these sites aids cell-type specification during development; however, aging prompts the loss of TF binding at these maturation-associated cCREs
- Late-life cCREs gaining accessibility throughout life display fewer cell-identity TFBSs but greater AP-1 binding
- Elevated levels of the activated AP-1 pioneer TF (in response to stimuli such as stress processes and growth/systemic factor cues) engage cCREs to increase chromatin accessibility to drive maturation and aging
- Increased AP-1 activity with aging prompts the redistribution of cell-type identity TFBSs from “closing” early-life cCREs to “opening” late-life cCREs, leading to the degradation of the well-orchestrated maturation process
- These findings suggest the redistribution of TFs toward late-life AP-1/TFBS-rich cCREs as a driving force behind the loss of accessibility at early-life cCREs and the alteration of genes linked to differentiation/development, metabolism, and stress responses, which could induce the appearance of many conserved phenotypes of aging
- Chromatin opening during maturation/aging functions synergistically between repressive epigenetic layer erosion (featuring DNA methylation loss or H3K27me3 depletion) and rising AP-1 expression levels
- Elevating AP-1 or depleting repressive H3K27me3 histone modification can trigger cCRE remodeling
AP-1’s pioneering function can drive maturation by reprogramming transcriptomes and cell functions via chromatin remodeling; however, increased AP-1 activity during aging hijacks this mechanism to disrupt cell identity and induce the well-known signs of aging. Therefore, the loss of epigenetic information alone does not appear to lead to age-associated phenotypes; instead, AP-1-mediated chromatin remodeling “decommissions” cell-identity TF-rich cCREs during aging.
For more on age-related AP1-driven chromatin remodeling hijacks maturation processes, see Cell Metabolism, July 2024.