Oncohistones: A new tool to dissect the role of H4R3 methylation in chromatin biology

Protein arginine methyltransferases (PRMTs) are enzymes that regulate the behaviour of proteins in the cell by adding a chemical methyl group to the amino acid arginine. This in turn regulates several important cellular processes and is significant for human health because PRMT levels are higher in cancer cells. This is important as it is now thought that cancer cells highjack PRMT functions and that this enables them to grow and evade chemotherapy treatments.

Because of this, PRMTs are now priority drug targets for several global pharmaceutical companies, however, the precise mechanisms by which PRMTs contribute to cancer and therapy resistance are still largely unknown. Without this knowledge, successful translation of PRMT drugs into the clinic will be challenging.

One of the first proteins identified as methylated by PRMTs was a protein called histone H4. Histones enable the packaging of DNA into a structure called chromatin, and their chemical modification is important for gene expression and DNA repair. Whilst it has been appreciated that PRMTs regulate these cellular functions, there has been an inability to define the actual significance of histone H4 methylation because PRMTs also methylate other proteins that are involved in gene expression and DNA repair. This has thus led to a substantial knowledge gap in an important area of cancer biology.

Some cancers are driven by mutations in histones, so called "oncohistones". We have taken advantage of a newly identified cancer-associated oncohistone mutation that occurs at a site targeted by PRMTs, providing us with a clinically relevant tool to understand how PRMT-mediated methylation of histone H4 regulates gene expression and genome stability.

In this project, we will investigate in fine detail how this oncohistone regulates cancer cell behaviour and if it is a driver event in cancer development. We will use state-of-the-art techniques to determine if effects of oncohistone expression are due to deregulated PRMT methylation or the substitution of an arginine amino acid for another. We will determine mechanistically how the oncohistone affects gene expression and DNA repair, and if the recruitment of proteins to DNA is altered.

The impact of our study is far reaching, clinically important and timely because PRMT inhibitors are in phase I clinical trials for cancer treatment. It will enable us to define the importance of PRMT-dependent histone H4 methylation and explore how it regulates gene expression and genome stability, and how this contributes to cancer growth and chemoresistance.

Crucially, it will provide insight into how PRMT inhibitors can be used in combination with agents that by modulating chromatin and/or DNA repair, thereby maximising their clinical potential and ultimately benefiting cancer patients.