Pioneer transcription factors such as OCT4 can target silent genes embedded in nucleosome-dense regions. How nucleosome interaction enables transcription factors to target chromatin and determine cell identity remains elusive. Here, we systematically dissect OCT4 to show that nucleosome binding is encoded within the DNA-binding domain and yet can be uncoupled from free-DNA binding. Furthermore, accelerating the binding kinetics of OCT4 to DNA enhances nucleosome binding. In cells, uncoupling nucleosome binding diminishes the ability of OCT4 to individually access closed chromatin, while more dynamic nucleosome binding results in expansive genome scanning within closed chromatin. However, both uncoupling and enhancing nucleosome binding are detrimental to inducing pluripotency from differentiated cells. Remarkably, stable interactions between OCT4 and nucleosomes are continuously required for maintaining the accessibility of pluripotency enhancers in stem cells. Our findings reveal how the affinity and residence time of OCT4–nucleosome complexes modulate chromatin accessibility during cell fate changes and maintenance.

先锋转录因子如 OCT4 可以靶向嵌入核小体密集区域的沉默基因。核小体相互作用如何使转录因子靶向染色质并确定细胞身份仍然难以捉摸。在这里，我们系统地剖析 OCT4 以表明核小体结合是在 DNA 结合域内编码的，但可以与游离 DNA 结合分离。此外，加速 OCT4 与 DNA 的结合动力学可增强核小体结合。在细胞中，解偶联核小体结合会降低 OCT4 单独访问闭合染色质的能力，而更动态的核小体结合会导致在闭合染色质内进行广泛的基因组扫描。然而，解偶联和增强核小体结合均不利于诱导分化细胞的多能性。值得注意的是，OCT4 和核小体之间的稳定相互作用是维持干细胞中多能性增强剂的可及性的持续需要。我们的研究结果揭示了 OCT4-核小体复合物的亲和力和停留时间如何在细胞命运变化和维持期间调节染色质的可及性。