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

Eimear Lagan¹, Dáire Gannon², Ademar Jesus Silva², Peter Bibawi³, Anthony M Doherty¹, Darragh Nimmo², Rachel McCole², Craig Monger², Giovani Luiz Genesi³, Aurelie Vanderlinden³, James A Innes³, Charlotte L E Jones⁴, Lu Yang⁵, Bryan Chen⁵, Guido van Mierlo⁶, Pascal W T C Jansen⁶, Chinmayi Pednekar⁷, Alexander Von Kriegsheim⁷, Kieran Wynne⁸, Francisco J Sánchez-Rivera⁹, Yadira M Soto-Feliciano⁹, Angel M Carcaboso¹⁰, Michiel Vermeulen¹¹, Giorgio Oliviero⁸, Chun-Wei Chen⁵, Richard E Phillips¹², Adrian P Bracken¹³, Gerard L Brien¹⁴

Affiliations

¹ Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
² Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
⁵ Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁶ Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
⁷ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK.
⁸ Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
⁹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Boston, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.
¹¹ Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
¹² Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: richard.phillips@pennmedicine.upenn.edu.
¹³ Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. Electronic address: adrian.bracken@tcd.ie.
¹⁴ Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK. Electronic address: gbrien@ed.ac.uk.

PMID: 40403727
PMCID: PMC12191925 (available on 2026-06-05)
DOI: 10.1016/j.molcel.2025.04.026

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

Eimear Lagan et al. Mol Cell. 2025.

. 2025 Jun 5;85(11):2110-2127.e7.

doi: 10.1016/j.molcel.2025.04.026. Epub 2025 May 21.

Authors

Affiliations

¹ Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
² Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
⁵ Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁶ Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
⁷ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK.
⁸ Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
⁹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Boston, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.
¹¹ Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
¹² Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: richard.phillips@pennmedicine.upenn.edu.
¹³ Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. Electronic address: adrian.bracken@tcd.ie.
¹⁴ Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK. Electronic address: gbrien@ed.ac.uk.

PMID: 40403727
PMCID: PMC12191925 (available on 2026-06-05)
DOI: 10.1016/j.molcel.2025.04.026

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.

Keywords: CBX4; EZH2; H3K27M; H3K27me3; PCGF4; PRC1; PRC2; Polycomb; diffuse intrinic pontine glioma; diffuse midline glioma.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, Bjerke L, Clarke M, Vinci M, Nandhabalan M, et al. (2017). Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell 32, 520–537 e525. 10.1016/j.ccell.2017.08.017. - DOI - PMC - PubMed
1. Jovanovich N, Habib A, Head J, Hameed F, Agnihotri S, and Zinn PO (2023). Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics. Neurooncol Adv 5, vdad040. 10.1093/noajnl/vdad040. - DOI - PMC - PubMed
1. Jones C, and Baker SJ (2014). Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer 14. 10.1038/nrc3811. - DOI - PMC - PubMed
1. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, and Ellison DW (2016). The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131, 803–820. 10.1007/s00401-016-1545-1. - DOI - PubMed
1. Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, Bechet D, Faury D, De Jay N, Ramkissoon LA, et al. (2014). Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46, 462–466. 10.1038/ng.2950. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical