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

Authors:

• Patrick, Ralph
• Naval-Sanchez, Marina
• Deshpande, Nikita
• Huang, Yifei
• Zhang, Jingyu
• Chen, Xiaoli
• Yang, Ying
• Tiwari, Kanupriya
• Esmaeili, Mohammadhossein
• Tran, Minh
• Mohamed, Amin R.
• Wang, Binxu
• Xia, Di
• Ma, Jun
• Bayliss, Jacqueline
• Wong, Kahlia
• Hun, Michael L.
• Sun, Xuan
• Cao, Benjamin
• Cottle, Denny L.
• Catterall, Tara
• Barzilai-Tutsch, Hila
• Troskie, Robin-Lee
• Chen, Zhian
• Wise, Andrea F.
• Saini, Sheetal
• Soe, Ye Mon
• Kumari, Snehlata
• Sweet, Matthew J.
• Thomas, Helen E.
• Smyth, Ian M.
• Fletcher, Anne L.
• Knoblich, Konstantin
• Watt, Matthew J.
• Alhomrani, Majid
• Alsanie, Walaa
• Quinn, Kylie M.
• Merson, Tobias D.
• Chidgey, Ann P.
• Ricardo, Sharon D.
• Yu, Di
• Jardé, Thierry
• Cheetham, Seth W.
• Marcelle, Christophe
• Nilsson, Susan K.
• Nguyen, Quan
• White, Melanie D.
• Nefzger, Christian M.

Details:

Cell Metabolism, Volume 36, Issue 8, 2024-08-06

Article Link: Click here

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.