Uckelmann Michael, Levina Vita, Taveneau Cyntia, Ng Xiao Han, Pandey Varun, Martinez Jasmine, Mendiratta Shweta, Houx Justin, Boudes Marion, Venugopal Hari, Trépout Sylvain, Fulcher Alex J, Zhang Qi, Flanigan Sarena, Li Minrui, Sierecki Emma, Gambin Yann, Das Partha Pratim, Bell Oliver, de Marco Alex, Davidovich Chen
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
Nat Struct Mol Biol. 2025 Mar;32(3):520-530. doi: 10.1038/s41594-024-01457-6. Epub 2025 Jan 15.
The compaction of chromatin is a prevalent paradigm in gene repression. Chromatin compaction is commonly thought to repress transcription by restricting chromatin accessibility. However, the spatial organization and dynamics of chromatin compacted by gene-repressing factors are unknown. Here, using cryo-electron tomography, we solved the three-dimensional structure of chromatin condensed by the polycomb repressive complex 1 (PRC1) in a complex with CBX8. PRC1-condensed chromatin is porous and stabilized through multivalent dynamic interactions of PRC1 with chromatin. Mechanistically, positively charged residues on the internally disordered regions of CBX8 mask negative charges on the DNA to stabilize the condensed state of chromatin. Within condensates, PRC1 remains dynamic while maintaining a static chromatin structure. In differentiated mouse embryonic stem cells, CBX8-bound chromatin remains accessible. These findings challenge the idea of rigidly compacted polycomb domains and instead provide a mechanistic framework for dynamic and accessible PRC1-chromatin condensates.
染色质的压缩是基因抑制中一种普遍存在的模式。通常认为染色质压缩通过限制染色质可及性来抑制转录。然而，由基因抑制因子压缩的染色质的空间组织和动态变化尚不清楚。在这里，我们使用冷冻电子断层扫描技术，解析了与CBX8形成复合物的多梳抑制复合物1（PRC1）压缩的染色质的三维结构。PRC1压缩的染色质是多孔的，并通过PRC1与染色质的多价动态相互作用得以稳定。从机制上讲，CBX8内部无序区域上的带正电残基掩盖了DNA上的负电荷，以稳定染色质的凝聚状态。在凝聚物中，PRC1保持动态，同时维持静态的染色质结构。在分化的小鼠胚胎干细胞中，与CBX8结合的染色质仍然可及。这些发现挑战了多梳结构域刚性压缩的观点，而是为动态且可及的PRC1-染色质凝聚物提供了一个机制框架。
