A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma
Year: 2025
Type: article
Abstract: Diffuse midline glioma (DMG) is a fatal childhood brain tumor characterized primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3). Paradoxically, PRC2 is essential in DMG cells, although the downstream molecular mechanisms are poorly understood. Here, we have discovered a specific form of canonical PRC1 (cPRC1) containing CBX4 and PCGF4 that 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.
Source: Molecular Cell
Authors: Eimear Lagan, Dáire Gannon, Ademar Jesus Silva, Peter Bibawi, Anthony M. Doherty, Darragh Nimmo, Rachel McCole, Craig Monger, Giovani Luiz Genesi, Aurelie Vanderlinden, James A. Innes, Charlotte L.E. Jones, Lu Yang, Bryan Chen, Guido van Mierlo, Pascal W.T.C. Jansen, Chinmayi Pednekar, Alexander Von Kriegsheim, Kieran Wynne, Francisco J. Sánchez-Rivera, Yadira M. Soto-Feliciano, Angel M. Carcaboso, Michiel Vermeulen, Giorgio Oliviero, Chun-Wei Chen, Richard E. Phillips, Adrian P. Bracken, Gerard L. Brien
Institutions: Trinity College Dublin, Edinburgh Cancer Research, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Abramson Cancer Center, University of Pennsylvania, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Radboud University Nijmegen, Radboud Institute for Molecular Life Sciences, Oncode Institute, University College Dublin, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Hospital Sant Joan de Déu Barcelona, The Netherlands Cancer Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: V Foundation for Cancer Research, Wellcome Trust, Worldwide Cancer Research, UK Research and Innovation, Irish Cancer Society, Irish Research Council for Science, Engineering and Technology, Science Foundation Ireland, Brain Tumour Charity, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, USAF Phillips Laboratory
Awards: G1478514203, A national platform for comprehensive molecular analysis underpinning chemistry, the bioeconomy, and precision oncology research: from molecules to microorganisms and humans., G2501400550, G2622785855, G2627835147, G339059223, Targeting underlying disease mechanisms in cancer using targeted protein degraders, a novel class of molecular therapeutic, G48802243, High resolution metabolite and peptide mass spectrometry, Understanding mechanisms of transcriptional regulation by chromatin adaptor proteins, G5566292360, G6033413389, G6070809149, G615304589, G6467675191, Deciphering mechanisms of transcriptional repression which drive midline glioma, Mechanism and therapeutic opportunities of targeting the Tudor domain
OpenAlex ID: W4410550774