%0 Journal Article
%T The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.
%A Patrick R
%A Naval-Sanchez M
%A Deshpande N
%A Huang Y
%A Zhang J
%A Chen X
%A Yang Y
%A Tiwari K
%A Esmaeili M
%A Tran M
%A Mohamed AR
%A Wang B
%A Xia D
%A Ma J
%A Bayliss J
%A Wong K
%A Hun ML
%A Sun X
%A Cao B
%A Cottle DL
%A Catterall T
%A Barzilai-Tutsch H
%A Troskie RL
%A Chen Z
%A Wise AF
%A Saini S
%A Soe YM
%A Kumari S
%A Sweet MJ
%A Thomas HE
%A Smyth IM
%A Fletcher AL
%A Knoblich K
%A Watt MJ
%A Alhomrani M
%A Alsanie W
%A Quinn KM
%A Merson TD
%A Chidgey AP
%A Ricardo SD
%A Yu D
%A Jardé T
%A Cheetham SW
%A Marcelle C
%A Nilsson SK
%A Nguyen Q
%A White MD
%A Nefzger CM
%J Cell Metab
%V 36
%N 8
%D 2024 Aug 6
%M 38959897
%F 31.373
%R 10.1016/j.cmet.2024.06.006
%X 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.