Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeutic targeting of senescence for health benefits. Here, we examined the possibility that the epigenetic state of enhancers determines senescent cell fate. We explored this by generating time-resolved transcriptomes and epigenome profiles during oncogenic RAS-induced senescence and validating central findings in different cell biology and disease models of senescence. Through integrative analysis and functional validation, we reveal links between enhancer chromatin, transcription factor recruitment and senescence competence. We demonstrate that activator protein 1 (AP-1) ‘pioneers’ the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells. Together, our findings enabled us to manipulate the senescence phenotype with potential therapeutic implications.

衰老细胞影响许多生理和病理生理过程。虽然已经确定了诱导衰老的特定遗传和表观遗传元件，但定义衰老能力、诱导和维持的动力学、表观遗传机制和调控网络仍然知之甚少，这妨碍了为了健康益处而有意针对衰老进行治疗。在这里，我们研究了增强子的表观遗传状态决定衰老细胞命运的可能性。我们通过在致癌 RAS 诱导的衰老过程中生成时间分辨转录组和表观基因组图谱并验证不同细胞生物学和衰老疾病模型的中心发现来探索这一点。通过综合分析和功能验证，我们揭示了增强子染色质、转录因子招募和衰老能力之间的联系。我们证明激活蛋白 1 (AP-1) “开拓”了衰老增强子景观，并定义了驱动衰老细胞转录程序的转录因子网络的组织原理。总之，我们的发现使我们能够操纵具有潜在治疗意义的衰老表型。