Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Cell Stem Cell. 2018 Aug 2;23(2):266-275.e6. doi: 10.1016/j.stem.2018.05.020. Epub 2018 Jun 14.
Transcription factor (TF)-mediated reprogramming to pluripotency is a slow and inefficient process, because most pluripotency TFs fail to access relevant target sites in a refractory chromatin environment. It is still unclear how TFs actually orchestrate the opening of repressive chromatin during the long latency period of reprogramming. Here, we show that the orphan nuclear receptor Esrrb plays a pioneering role in recruiting the core pluripotency factors Oct4, Sox2, and Nanog to inactive enhancers in closed chromatin during the reprogramming of epiblast stem cells. Esrrb binds to silenced enhancers containing stable nucleosomes and hypermethylated DNA, which are inaccessible to the core factors. Esrrb binding is accompanied by local loss of DNA methylation, LIF-dependent engagement of p300, and nucleosome displacement, leading to the recruitment of core factors within approximately 2 days. These results suggest that TFs can drive rapid remodeling of the local chromatin structure, highlighting the remarkable plasticity of stable epigenetic information.
转录因子 (TF) 介导的重编程为多能性是一个缓慢且低效的过程，因为大多数多能性 TF 无法在有抵抗力的染色质环境中访问相关的靶位点。目前尚不清楚 TF 如何在重编程的长时间潜伏期内实际协调抑制性染色质的打开。在这里，我们表明孤儿核受体 Esrrb 在重编程上胚层干细胞过程中，在封闭染色质内招募核心多能因子 Oct4、Sox2 和 Nanog 到无活性增强子时发挥了先驱作用。Esrrb 结合到含有稳定核小体和高甲基化 DNA 的沉默增强子上，这些核小体和高甲基化 DNA 是核心因子无法接近的。Esrrb 结合伴随着局部 DNA 甲基化的丢失、LIF 依赖性 p300 的参与和核小体位移，导致核心因子在大约 2 天内被招募。这些结果表明，TF 可以驱动局部染色质结构的快速重塑，突出了稳定表观遗传信息的显著可塑性。
