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