Shen Yunfan, Liu Yanhong, Guo Maochao, Mao Song, Chen Rui, Wang Mengran, Li Zhengbo, Li Yue, Chen Wan, Chen Fang, Wu Baixing, Wang Chongyuan, Chen Wei, Cui Huanhuan, Yuan Kai, Huang Hongda
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
Nat Struct Mol Biol. 2025 May 16. doi: 10.1038/s41594-025-01559-9.
DEK is a highly conserved chromatin-associated oncoprotein that has important roles in regulating chromatin dynamics and stem cell fate. Dysregulation of DEK is associated with stem cell dysfunction and cancers, including acute myeloid leukemia. Despite its importance in chromatin regulation, the structural mechanisms underlying DEK's interaction with chromatin and its influence on gene regulation remain poorly understood. Here we combined cryogenic electron microscopy (cryo-EM), biochemical and cellular approaches to investigate the molecular mechanisms and functional importance of DEK's interaction with chromatin. Our cryo-EM structures reveal the structural basis of the DEK-nucleosome interaction. Biochemical and cellular results demonstrate that this interaction is crucial for DEK deposition onto chromatin. Furthermore, our results reveal that DEK safeguards mouse embryonic stem cells from acquiring primitive endoderm fates by modulating the repressive histone mark H3K27me3. Together, our study provides crucial molecular insights into the structure and function of DEK, establishing a framework for understanding its roles in chromatin biology and cell fate determination.
DEK是一种高度保守的与染色质相关的癌蛋白，在调节染色质动力学和干细胞命运方面具有重要作用。DEK失调与干细胞功能障碍和癌症相关，包括急性髓系白血病。尽管其在染色质调控中很重要，但DEK与染色质相互作用的结构机制及其对基因调控的影响仍知之甚少。在这里，我们结合低温电子显微镜（cryo-EM）、生化和细胞方法来研究DEK与染色质相互作用的分子机制和功能重要性。我们的低温电子显微镜结构揭示了DEK-核小体相互作用的结构基础。生化和细胞结果表明，这种相互作用对于DEK在染色质上的沉积至关重要。此外，我们的结果表明，DEK通过调节抑制性组蛋白标记H3K27me3来保护小鼠胚胎干细胞不获得原始内胚层命运。总之，我们的研究为DEK的结构和功能提供了关键的分子见解，建立了一个理解其在染色质生物学和细胞命运决定中作用的框架。
