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

First Author  Patrick R Year  2024
Journal  Cell Metab Volume  36
Issue  8 Pages  1858-1881.e23
PubMed ID  38959897 Mgi Jnum  J:359895
Mgi Id  MGI:7704960 Doi  10.1016/j.cmet.2024.06.006
Citation  Patrick R, et al. (2024) The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening. Cell Metab
abstractText  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.
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