Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.

中文翻译：

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转录因子在细胞重编程过程中协调基因组拓扑和基因调控之间的动态相互作用。

已知染色体结构会影响基因表达，但其在控制细胞命运中的作用仍知之甚少。通过转录因子 (TF) OCT4、SOX2、KLF4 和 MYC 将体细胞重编程为多能干细胞 (PSC)，这为解决这个问题提供了机会，但由于响应细胞比例低而受到严重限制。我们最近开发了一种高效的重编程方案，可将体细胞同步转化为多能干细胞。在这里，我们使用该系统将基因组拓扑的时间分辨变化与基因表达、TF 结合和染色质状态动态相结合。结果表明，转录因子通常在基因表达发生变化之前，在多个结构水平上驱动拓扑基因组重组。位点特异性拓扑障碍的去除可以解释为什么多能性基因在重编程过程中顺序激活，而不是同时激活。总之，我们的结果表明基因组拓扑结构是在哺乳动物中实施转录程序和细胞命运的指导力量。