Study identifies molecular process behind fatal childhood brain cancer

Published in Molecular Cell, a 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 instead 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.