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.
摘要：
衰老与发育之间的机械联系在很大程度上尚未探索。通过分析22种小鼠细胞类型的年龄相关染色质和转录变化，与以前的小鼠和人类生物体成熟数据集一起分析，我们发现了两个过程共有的转录因子结合位点（TFBS）特征。早期候选顺式调控元件(cCREs)，在成熟和衰老过程中逐渐失去可及性，富集了细胞类型标识TFBS。相反，在整个生命中获得可及性的cCRE具有较低的细胞身份TFBSs丰度，但激活蛋白1（AP-1）水平升高。我们暗示TF对这些富含AP-1TFBS的cCRE的再分配，与细胞身份TFs的轻度下调协同作用，驱动早期cCRE可及性丧失和改变发育和代谢基因表达。这种重塑可以通过升高AP-1或耗尽抑制性H3K27me3来触发。我们建议AP-1连接的染色质开放通过破坏细胞身份TFBS丰富的cCREs来驱动生物体成熟，从而重新编程转录组和细胞功能，一种通过持续开放染色质在衰老过程中劫持的机制。
