Researchers have discovered an important molecular mechanism underlying diffuse midline glioma - an aggressive and currently incurable brain tumour that mostly affects children. Gerry Brien and Eimear Lagan Diffuse midline glioma (DMG) is driven by a mutation in a protein called histone H3, which causes widespread disruptions in how genes are turned on and off. Although scientists have known that this mutation leads to abnormal gene silencing, exactly how this happens has remained a mystery - until now.Researchers at the Institute of Genetics and Cancer (IGC) have identified a rare but powerful protein complex that plays a central role in this gene repression. The complex, made up of several proteins including CBX4 and PCGF4, belongs to a group of gene-silencing machines called cPRC1. Surprisingly, the CBX4/PCGF4 version makes up less than 5% of these complexes in tumour cells but turns out to be essential for cancer growth.This specific complex binds to certain areas of DNA and switches off genes that normally help cells mature or stop dividing. By doing this, it helps the tumour cells stay in a primitive, fast-growing state. When the researchers disabled CBX4 or PCGF4 in lab-grown DMG cells or mouse models, the tumours stopped growing. Other similar proteins did not have the same effect, showing that this particular complex has a unique role in the disease.These findings point to a new and highly specific weakness in DMG tumours. Rather than targeting broad systems in the cell, future treatments could focus on disrupting this small but critical protein complex, potentially leading to more effective and safer therapies for children with this devastating cancer. DMG is a very challenging, incurable disease with an average survival time post diagnosis of nine months. We have discovered an important molecular mechanism underlying the disease and while we are not at a point where we can exploit this with therapies or drugs for patients, it’s an important early step towards getting there. Dr Gerry Brien Chancellor’s Fellow, Edinburgh Cancer Research This has been a significant collaborative effort, involving labs in multiple countries. This kind of joint effort, bringing together different sets of expertise will continue to be essential for us to develop these new therapies. This will be challenging but exciting work. Dr Eimear Lagan Postdoctoral researcher Read the study in Cell Press (external link) Gerry Brien Research Group Tags 2025 Publication date 22 May, 2025