Li Jingxin, Ravindran Pavithran T, O'Farrell Aoife, Busch Gianna T, Boe Ryan H, Niu Zijian, Woo Sean, Dunagin Margaret C, Jain Naveen, Goyal Yogesh, Sarma Kavitha, Herlyn Meenhard, Raj Arjun
Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Cancer Biology Program, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
bioRxiv. 2024 Jul 25:2024.07.25.604999. doi: 10.1101/2024.07.25.604999.
Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that melanoma cells can form and maintain cellular memories during the acquisition of therapy resistance that exhibit characteristics of cellular learning and are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that resistance was not purely selective. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility showed concomitant persistence. A two-color AP-1 reporter system showed that these memories are encoded in , constituting an example of activating epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance.
细胞对环境刺激的反应通常被认为是由基因编码程序控制的。我们证明，黑色素瘤细胞在获得治疗抗性的过程中可以形成并维持细胞记忆，这些记忆具有细胞学习的特征，并依赖于转录因子AP-1。我们表明，暴露于低剂量治疗的细胞会适应并对高剂量产生抗性，这表明抗性并非纯粹是选择性的。治疗本身会导致将瞬时基因表达编码到细胞记忆中，并且这种编码既发生在瞬时诱导的表达中，也发生在概率性出现的表达中。染色质可及性表现出相应的持久性。双色AP-1报告系统表明，这些记忆是在……中编码的，构成了激活表观遗传学的一个例子。我们的研究结果确立了细胞记忆的形成和维持是治疗抗性发展过程中基因调控的一个关键方面。
