A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma

Published: 23 April 2025| Version 2 | DOI: 10.17632/ft63v4p2cp.2
Contributors:
Eimear Lagan, Dáire Gannon, AJ Silva, Peter Bibawi, Anthony Doherty, Darragh Nimmo, Rachel McCole, Craig Monger, Giovani Genesi, Aurelie Vanderlinden, James Innes, Charlotte Jones, Lu Yang, Bryan Chen, Guido van Mierlo, Pascal Jansen, Chinmayi Pednekar, Alexander von Kriegsheim, Keiran Wynne, Francisco Sánchez-Rivera, Yadira Soto-Feliciano, Michiel Vermeulen, Giorgio Oliviero, Chun-Wei Chen, Richard Phillips, Adrian Bracken, Gerard Brien

Description

Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3. Paradoxically, PRC2 is essential in DMG cells, although the downstream molecular mechanisms are poorly understood. Here, we’ve discovered a specific form of canonical PRC1 (cPRC1) containing CBX4 and PCGF4 drives oncogenic gene repression downstream of H3K27me3 in DMG cells. Via a novel functional region, CBX4 preferentially associates with PCGF4 containing cPRC1. The characteristic H3K27me3 landscape in DMG rewires the distribution of cPRC1 complexes, with CBX4/PCGF4-cPRC1 accumulating at H3K27me3 enriched CpG islands. Despite comprising <5% of cPRC1 in DMG cells, the unique repressive functions of CBX4/PCGF4-cPRC1 are essential for DMG growth. Our findings link the altered distribution of H3K27me3 to imbalanced cPRC1 function, which drives oncogenic gene repression in DMG, highlighting potential therapeutic opportunities for this incurable childhood brain cancer.

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Institutions

  • The University of Edinburgh

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Western Blot

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