Chemical biology toolbox proves handy in epigenetic exploration
Scientists from the Monash Biomedicine Discovery Institute (BDI), along with collaborators from the University of Toronto, have revealed a previously unknown use for an anti-cancer therapeutic in the immune system.
The team of scientists found that the drug SGC0946, which blocks the activity of a protein called DOT1L, can modulate the function of T cells–immune cells critical for immunity to infections–rendering the T cells more inflammatory. Inflammatory T cells are critical for controlling infections by viruses and bacteria, suggesting that blocking DOT1L could lead to enhanced immunity for patients. However, blocking the protein could also promote too much inflammation and exacerbate autoimmune diseases, the researchers cautioned.
The study was published recently in Nature Communications.
The researchers made use of a ‘chemical probe’ collection generated and curated by The Structural Genomics Consortium, a public-private partnership based in Toronto and Oxford, UK. This collection is an open-access and free to use library of drugs for which an effective use hasn’t been found or proven, but which may help generate new knowledge or use. Specifically, this collection supports the study of methylation-mediated signalling in epigenetics, inflammation and beyond.
The researchers, led by the Monash BDI’s Professor Colby Zaph, and the University of Toronto’s Dr Peter Brown and Professor Cheryl Arrowsmith, were using the chemical probe collection in an open-ended exploration of the role of protein methyltransferases (PMTs) in the outcome of immune response. Methylation is one of the layers of control exerted on genes epigenetically.
“It was a fishing expedition that pulled out a really big fish,” Professor Zaph said.
“We’ve identified this protein, DOT1L, that nobody really thought about in the context of T cells. Now we know that if you block its function in T cells we can significantly modulate the production of inflammatory cytokines,” he said.
“The potential ramifications are huge.”
T cells are critical for developing immunity to all classes of infections, from viruses to parasites, and with the emergence of tumour immunotherapies, have been shown to play an important role in fighting cancer. However, unregulated T cell responses are also associated with a wide range of inflammatory diseases including inflammatory bowel disease, asthma, diabetes and multiple sclerosis.
“This is the first time that this has been described – it opens up a completely area of research in T cell biology. The influence of DOT1L in T cell mediated immunity and disease has never been examined. This is now our focus,” first author Dr Sebastian Scheer said.
The drug that blocks the activity of DOT1L is an approved anti-cancer drug that has gone through phase I and II clinical trials but which has not been tested for its effect on other diseases. The research being conducted by the collaborators at this stage was about creating fundamental knowledge about how T cells get activated, Professor Zaph said.
“The next step is to see if blocking DOT1L during inflammatory disease offers a new therapeutic strategy,” he said.
Professor Zaph said the study, which also pointed to several other enzymes worth investigating, highlighted the value of the collection as an investigative toolbox.
“This collection of inhibitors allows any researcher to directly test the role of these PMTs in their own model systems. The possibilities are endless and something surprising and important is likely to arise from this,” he said.
Read the full paper in Nature Communications titled A chemical biology toolbox to study protein methyltransferases and epigenetic signaling.
About the Monash Biomedicine Discovery Institute Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.