近日，澳大利亚昆士兰大学Christian M. Nefzger研究团队探明，早期生命基因调控元件的活动在衰老过程中被广泛的AP-1相关染色质开放所劫持。2024年7月2日，国际知名学术期刊《细胞—代谢》发表了这一成果。

通过分析22种小鼠细胞类型中与年龄相关的染色质和转录变化，并与先前的小鼠和人类组织成熟数据集一起分析，该研究组发现了两个过程中共同的转录因子结合位点(TFBS)特征。早期生命候选顺式调控元件(cCREs)在成熟和衰老过程中逐渐失去可及性，但它们富集了细胞类型特异性转录因子结合位点。相反，在整个生命过程中获得可接近性的顺式调控元件，具有较低的细胞特异性转录因子结合位点丰度，但激活蛋白1 (AP-1)水平升高。

该团队认为，转录因子向这些富含AP-1 转录因子结合位点富集的顺式调控元件再分配，与细胞特异性转录因子的轻度下调协同作用，导致早期顺式调控元件可及性丧失，并改变发育和代谢基因表达。这种重塑可以通过提高AP-1或消耗抑制性H3K27me3来触发。研究团队提出AP-1连接的染色质通过破坏富含转录因子结合位点的顺式调控元件的细胞身份，来驱动生物体成熟，从而重新编程转录组和细胞功能，这是一种通过持续染色质打开在衰老过程中被劫持的机制。

据了解，衰老和发育之间的机制联系在很大程度上尚未被探索。

附：英文原文

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

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

Issue&Volume: 2024-07-02

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.

DOI: 10.1016/j.cmet.2024.06.006

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00231-6