Dynamic PRC1-CBX8 stabilizes a porous structure of chromatin condensates

Michael Uckelmann; Vita Levina; Cyntia Taveneau; Xiao Han Ng; Varun Pandey; Jasmine Martinez; Shweta Mendiratta; Justin Houx; Marion Boudes; Hari Venugopal; Sylvain Trépout; Alex J Fulcher; Qi Zhang; Sarena Flanigan; Minrui Li; Emma Sierecki; Yann Gambin; Partha Pratim Das; Oliver Bell; Alex de Marco; Chen Davidovich

doi:10.1038/s41594-024-01457-6

Dynamic PRC1-CBX8 stabilizes a porous structure of chromatin condensates

Nat Struct Mol Biol. 2025 Jan 15. doi: 10.1038/s41594-024-01457-6. Online ahead of print.

Authors

Michael Uckelmann¹, Vita Levina¹, Cyntia Taveneau^{1

2}, Xiao Han Ng¹, Varun Pandey³, Jasmine Martinez⁴, Shweta Mendiratta⁴, Justin Houx⁵, Marion Boudes¹, Hari Venugopal⁶, Sylvain Trépout⁶, Alex J Fulcher⁷, Qi Zhang¹, Sarena Flanigan¹, Minrui Li^{1

8}, Emma Sierecki⁵, Yann Gambin⁵, Partha Pratim Das³, Oliver Bell⁴, Alex de Marco^{1

2

9}, Chen Davidovich^{10

11}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
² ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
³ Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁴ Departments of Biochemistry and Molecular Medicine, and Stem Cell and Regenerative Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ EMBL Australia Node for Single Molecule Science and School of Biomedical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.
⁶ Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Monash, Victoria, Australia.
⁷ Monash Micro Imaging, Monash University, Clayton, Victoria, Australia.
⁸ Faculty of Information Technology, Monash University, Clayton, Victoria, Australia.
⁹ Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
¹⁰ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. Chen.Davidovich@monash.edu.
¹¹ EMBL-Australia, Clayton, Victoria, Australia. Chen.Davidovich@monash.edu.

PMID: 39815045
DOI: 10.1038/s41594-024-01457-6

Abstract

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.