An international group of scientists has identified a key molecular process that drives a deadly form of childhood brain cancer, potentially offering a much-needed new therapeutic target.

Published in the journal Molecular Cell, the new study has revealed how a rare but devastating childhood brain cancer—called diffuse midline glioma (DMG)—hijacks the cell's gene control machinery to fuel its growth. The findings could point the way to urgently needed new treatments for this currently incurable disease.

DMG is a tumour that develops deep in the brain and primarily affects children and young adults. Nearly all cases carry a key genetic change: a mutation in a protein called histone H3, which helps package DNA inside cells. This mutation disrupts a crucial chemical mark—known as H3K27me3—that normally acts like a stop sign to silence genes.

Scientists had long believed this disruption caused genes to turn on when they shouldn't. But in a surprising twist, the researchers behind the new study found that parts of this "stop sign" system still remain—and the tumour actually depends on them to survive.

Using cutting-edge genetic screens and molecular tools, the team discovered that a very specific gene-silencing complex—called CBX4/PCGF4-cPRC1—is essential for the tumour's growth. Although it makes up less than 5% of the related silencing machinery in the cancer cells, this particular complex plays an outsized role in shutting down genes that would otherwise prevent the tumour from growing.

The study also revealed how a previously unknown region in the CBX4 protein helps it form a special partnership with PCGF4, enabling this harmful gene repression.

"Although this form of PRC1 gene-silencing complex represents less than 5% of PRC1 in these tumours, our research shows it is essential for tumour growth," said Professor Adrian Bracken, co-lead investigator on the study from Trinity College Dublin's Smurfit Institute of Genetics.

"By specifically targeting this rare form of PRC1, it may be possible to develop more precise treatments that minimise side effects that can arise with broader-acting therapies."

Dr. Gerard Brien, co-lead investigator from the University of Edinburgh, added, "This discovery sheds light on a key mechanism driving DMG and identifies CBX4 as a promising drug target. Our findings suggest that interfering with CBX4's interaction with chromatin or its partner protein PCGF4 could disrupt the tumour's gene-silencing machinery—potentially paving the way for new treatment strategies against this devastating disease."

This work was led by two outstanding former Ph.D. Researchers from the Bracken Lab, Dr. Eimear Lagan and Dr. Daire Gannon, collaborated closely throughout their doctoral studies to address this challenging disease. Dr. Lagan completed her Ph.D. Under the joint supervision of Dr. Bracken and Dr. Gerry Brien, she conducted her final research in Dr. Brien's lab at the University of Edinburgh.