News / 9 June 2024

EMBL Australia researchers based at Monash University have unlocked some secrets about the way a protein works to switch genes off, in a discovery that could improve the understanding of how diseases such as cancer progress.

All genes produce RNA (ribonucleic acid), which is present in all living cells and plays the role of translating our genes into proteins that allow our different cell types to develop and function. But RNA has been postulated to play a number of additional roles, including regulating proteins that are involved in switching genes on and off. Such gene-repressor proteins form enzymatic complexes— called chromatin modifiers—and one of them is central for gene repression and is called PRC2.

PRC2 is required for normal embryonic development and is dysregulated in many types of cancer and in several developmental disorders. It has long been hypothesised that RNA binds to PRC2 and brings it to specific genes that need to be turned off, so cells can undergo their normal functions. This hypothesis has been at the centre of fierce debate among scientists for over 15 years.

Published recently in Nature Genetics, co-senior author Associate Professor Chen Davidovich, an EMBL Australia Group Leader and Lab Head at the Monash Biomedicine Discovery Institute (BDI), explained the findings.

“We found a site in PRC2 that binds to both RNA and DNA,” A/Prof Davidovich said. “Through detailed experiments, we found that some of the activities of PRC2 that were previously thought to be driven because of interactions between PRC2 and RNA can, instead, be explained by interactions between PRC2 and DNA. Conversely, we did not find evidence that RNA is required to substantially dictate the activity of PRC2.”

To provide an analogy, genes can be thought of as the roadmap for how we develop, allowing embryos to ‘drive’ stem cells into forming all the different cell types in our bodies. In that analogy, PRC2 is a handbrake that ‘parks’ cells safely once they have obtained their genetic identity. Just as a car without a handbrake can dangerously slide downhill, if PRC2 does not work properly, severe developmental disorders and cancer can be the end-point.

“Our study shows that a large surface in PRC2 is critical to bind to DNA in order to ‘park’ cells in their desired state. Mutations in and around this surface have been found to be associated with a number of different cancers and in developmental disorders, such as Weaver syndrome,” he said.

“Our finding that RNA binds to a DNA-binding surface of PRC2 suggests that this may also be the case for many other chromatin modifying enzymes. This may allow one to set hypotheses on how such chromatin modifying enzymes bind to RNA and DNA and then help to design the experiments that are needed in order to test them. Down the line, this could direct our understanding about how changes in such RNA and DNA binding sites within chromatin modifiers may lead to developmental disorders and cancer.”

The big question for the field that remains is why does RNA bind to chromatin modifying enzymes such as PRC2? It is essential that we figure this question out.

The co-first authors are Dr Emma Gail and Dr Evan Healy and the study was co-led by EMBL Australia Group Leaders Dr Qi Zhang and Associate Professor Davidovich.

Read the full paper in Nature Genetics titled: Inseparable RNA binding and chromatin modification activities of a nucleosome-interacting surface in EZH2 DOI: 10.1038/s41588-024-01740-8

This story originally appeared on the Monash Biomedicine Discovery Institute website.

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