1. The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.
- Author
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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, and Nefzger CM
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Binding Sites, Aging genetics, Aging metabolism, Transcription Factor AP-1 metabolism, Chromatin metabolism
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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