A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma.
Por:
Lagan E, Gannon D, Silva AJ, Bibawi P, Doherty AM, Nimmo D, McCole R, Monger C, Genesi GL, Vanderlinden A, Innes JA, Jones CLE, Yang L, Chen B, van Mierlo G, Jansen PWTC, Pednekar C, Von Kriegsheim A, Wynne K, Sánchez-Rivera FJ, Soto-Feliciano YM, Carcaboso AM, Vermeulen M, Oliviero G, Chen CW, Phillips RE, Bracken AP and Brien GL
Publicada:
5 jun 2025
Ahead of Print:
21 may 2025
Resumen:
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.
Filiaciones:
Lagan E:
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
Gannon D:
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Silva AJ:
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Bibawi P:
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
Doherty AM:
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
Nimmo D:
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
McCole R:
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Monger C:
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Genesi GL:
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
Vanderlinden A:
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
Innes JA:
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
Jones CLE:
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
Yang L:
Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Chen B:
Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
van Mierlo G:
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
Jansen PWTC:
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
Pednekar C:
Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK
Von Kriegsheim A:
Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK
Wynne K:
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland
Sánchez-Rivera FJ:
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Boston, MA, USA
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
Soto-Feliciano YM:
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Boston, MA, USA
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
Carcaboso AM:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Vermeulen M:
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
Oliviero G:
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland
Chen CW:
Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Phillips RE:
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
Bracken AP:
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Brien GL:
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
Green Submitted, Green Published, hybrid
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