Pioneer transcription factors have the ability to access DNA in compacted chromatin¹. Multiple transcription factors can bind together to a regulatory element in a cooperative way, and cooperation between the pioneer transcription factors OCT4 (also known as POU5F1) and SOX2 is important for pluripotency and reprogramming^2,3,4. However, the molecular mechanisms by which pioneer transcription factors function and cooperate on chromatin remain unclear. Here we present cryo-electron microscopy structures of human OCT4 bound to a nucleosome containing human LIN28B or nMATN1 DNA sequences, both of which bear multiple binding sites for OCT4. Our structural and biochemistry data reveal that binding of OCT4 induces changes to the nucleosome structure, repositions the nucleosomal DNA and facilitates cooperative binding of additional OCT4 and of SOX2 to their internal binding sites. The flexible activation domain of OCT4 contacts the N-terminal tail of histone H4, altering its conformation and thus promoting chromatin decompaction. Moreover, the DNA-binding domain of OCT4 engages with the N-terminal tail of histone H3, and post-translational modifications at H3K27 modulate DNA positioning and affect transcription factor cooperativity. Thus, our findings suggest that the epigenetic landscape could regulate OCT4 activity to ensure proper cell programming.

先锋转录因子能够接触压缩染色质中的 DNA ¹ 。多个转录因子可以以协作方式与调控元件结合在一起，先驱转录因子 OCT4（也称为 POU5F1）和 SOX2 之间的协作对于多能性和重编程非常重要^2,3,4 。然而，先驱转录因子在染色质上发挥作用和合作的分子机制仍不清楚。在这里，我们展示了人类 OCT4 与含有人类LIN28B或 n MATN1 DNA 序列的核小体结合的冷冻电子显微镜结构，这两者都具有 OCT4 的多个结合位点。我们的结构和生物化学数据表明，OCT4 的结合会诱导核小体结构的变化，重新定位核小体 DNA，并促进其他 OCT4 和 SOX2 与其内部结合位点的协同结合。 OCT4 的灵活激活结构域接触组蛋白 H4 的 N 末端尾部，改变其构象，从而促进染色质解压缩。此外，OCT4 的 DNA 结合结构域与组蛋白 H3 的 N 末端尾部结合，H3K27 的翻译后修饰可调节 DNA 定位并影响转录因子的协同性。因此，我们的研究结果表明表观遗传景观可以调节 OCT4 活性以确保正确的细胞编程。