美国圣裘德儿童研究医院Mario Halic课题组发现，组蛋白修饰调节先锋转录因子的合作性。这一研究成果于2023年5月24日在线发表在国际学术期刊《自然》上。

研究人员提出了人类OCT4与含有人类LIN28B或nMATN1 DNA序列的核小体结合的冷冻电镜结构，这两个核小体都有OCT4的多个结合点。结构和生物化学数据显示，OCT4的结合引起了核小体结构的变化，重新定位了核小体DNA，并促进了额外的OCT4和SOX2与它们的内部结合点的合作。OCT4的柔性激活结构域接触组蛋白H4的N端尾巴，改变其构象，从而促进染色质的解压。此外，OCT4的DNA结合结构域与组蛋白H3的N端尾巴相接触，H3K27的翻译后修饰调节DNA定位并影响转录因子的合作性。因此，这些研究结果表明，表观遗传景观可以调节OCT4的活性，以确保适当的细胞编程。

据悉，先锋转录因子有能力进入压实染色质中的DNA。多个转录因子可以以合作的方式结合在一起，先锋转录因子OCT4（也称为POU5F1）和SOX2之间的合作对多能性和重编程很重要。然而，先锋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。

附：英文原文

Title: Histone modifications regulate pioneer transcription factor cooperativity

Author: Sinha, Kalyan K., Bilokapic, Silvija, Du, Yongming, Malik, Deepshikha, Halic, Mario

Issue&Volume: 2023-05-24

Abstract: 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 reprogramming2,3,4. 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.

DOI: 10.1038/s41586-023-06112-6

Source: https://www.nature.com/articles/s41586-023-06112-6