早年基因调控元件的活性在衰老过程中通过 AP-1 链接的染色质开放被劫持

IF 27.7 1区 生物学 Q1 CELL BIOLOGY
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, Christian M. Nefzger
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引用次数: 0

摘要

衰老与发育之间的机理联系在很大程度上尚未被探索。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,并结合以前的小鼠和人类生物体成熟数据集进行分析,我们发现了这两个过程共有的转录因子结合位点(TFBS)特征。生命早期的候选顺式调控元件(cCRE)在成熟和衰老过程中逐渐失去可及性,而细胞类型特征 TFBS 则富集其中。相反,在整个生命过程中获得可及性的 cCREs 中,细胞特征 TFBS 的丰度较低,但激活蛋白 1(AP-1)的水平较高。我们认为,TF向这些富含AP-1 TFBS的cCRE重新分配,与细胞身份TF的轻度下调协同作用,推动了生命早期cCRE可及性的丧失,并改变了发育和代谢基因的表达。这种重塑可通过提高 AP-1 或消耗抑制性 H3K27me3 来触发。我们提出,与 AP-1 相关的染色质开放通过破坏富含细胞特征 TFBS 的 cCRE 来驱动生物体的成熟,从而重新编程转录组和细胞功能,而这种机制在衰老过程中会通过持续的染色质开放被劫持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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.

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来源期刊
Cell metabolism
Cell metabolism 生物-内分泌学与代谢
CiteScore
48.60
自引率
1.40%
发文量
173
审稿时长
2.5 months
期刊介绍: Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.
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