CHD4 – a protein that regulates the tumour

Dr. Joana G. Marques

Universitäts-Kinderspital Zürich

Cancer remains the most common cause of death in children due to disease. Paediatric tumours are frequently closely linked to epigenetic disorders, both in their development and progression. In this process, it is not the DNA sequence itself that is affected by changes in the cell nucleus, but the three-dimensional structure of the chromosomes, which influences gene activity. This is why our understanding of epigenetic factors is central to the development of treatment strategies for tumours. 

The research team led by Joana Marques is also focussing on this kind of problem: The protein CHD4 is involved in the modelling of the chromosomal material (chromatin) and thus in the epigenetic regulation of gene activity, DNA repair and controlling cell division. It contributes towards the development of rhabdomyosarcoma, a rare, but dangerous paediatric cancer. With the aid of a number of genome sequencing techniques, the Zurich research group demonstrated for the first time that CHD4 - even though it is not mutated in this specific cancer - is essential to the survival of the cells in this tumour. This is because CHD4 supports the actual tumour driver of this cancer, the fusion transcription factor PAX3-FOXO1, by regulating specific gene regions (super-enhancers). Furthermore, they established that other types of malignant cancer rely on the active support of CHD4, not only in children, but also in adults.

The results of this study expand our knowledge on the role of epigenetic control in tumours and they are particularly important in the context of paediatric tumours. Shutting down CHD4 activity has the potential to open up research into new therapeutic options for paediatric forms of cancer.

NuRD subunit CHD4 regulates super-enhancer accessibility in rhabdomyosarcoma and represents a general tumor dependency. Joana G. Marques, Berkley E Gryder, Blaz Pavlovic, Yeonjoo Chung, Quy A Ngo, Fabian Frommelt, Matthias Gstaiger, Young Song, Katharina Benischke, Dominik Laubscher, Marco Wachtel, Javed Khan, Beat W Schäfer. 
eLife. 2020 Aug 3;9:e54993. doi: 10.7554/eLife.54993.