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

in Molecular cell by 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

TLDR

  • Researchers identified a specific form of PRC1 that drives oncogenic gene repression in DMG cells, highlighting potential therapeutic opportunities.
  • The CBX4/PCGF4-cPRC1 complex is essential for DMG growth, despite comprising <5% of cPRC1.
  • The study's findings suggest a new therapeutic approach for DMG, targeting or modulating the CBX4/PCGF4-cPRC1 complex.

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.

Overview

  • The study focuses on diffuse midline glioma (DMG), a fatal childhood brain tumor characterized by mutant histone H3 (H3K27M).
  • The study aims to understand the downstream molecular mechanisms of H3K27M in DMG cells.
  • The primary objective is to identify potential therapeutic opportunities for DMG, an incurable childhood brain cancer.

Comparative Analysis & Findings

  • The study discovered a specific form of canonical PRC1 (cPRC1) containing CBX4 and PCGF4 that drives oncogenic gene repression in DMG cells.
  • The CBX4/PCGF4-cPRC1 complex accumulates at H3K27me3-enriched CpG islands in DMG cells.
  • Despite comprising <5% of cPRC1 in DMG cells, the unique repressive functions of CBX4/PCGF4-cPRC1 are essential for DMG growth.

Implications and Future Directions

  • The findings suggest that the altered distribution of H3K27me3 in DMG cells is linked to imbalanced cPRC1 function, which drives oncogenic gene repression.
  • This insight highlights potential therapeutic opportunities for DMG, such as targeting or modulating the CBX4/PCGF4-cPRC1 complex.
  • Future studies may focus on developing targeted therapies for DMG, exploring the potential for cPRC1 modulation or inhibition to treat this incurable childhood brain cancer.
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