The study, published in the journal Cell, marks a step forward in the field of epigenetics and its impact on health and disease.
Epigenetics, the study of how genes are turned on or off without changing the DNA itself, is central to this process. It involves chemical tags on DNA and proteins called histones, which help manage gene activity. The tags need to be accurately passed on when cells divide, so the new cells function just like their parent cells.
The research, led by Professors Genevieve Thon and Anja Groth at the University of Copenhagen, found that Mrc1 is essential for this inheritance. During cell division, Mrc1 ensures that histones, carrying these chemical tags, are evenly distributed to both new copies of the DNA, maintaining the cell's identity and function.
"During my PhD work at the Department of Biology, we knew this protein was important for maintaining the heterochromatic state in cells. We had a good idea of how it worked, but while we had experimental data, we didn't have the tools in our lab to confirm it on a molecular level," says Sebastian Charlton, now Postdoc at the Novo Nordisk Foundation Center for Protein Research (CPR), who is the shared first author of the study.
To get those tools, Dr. Charlton teamed up with Assistant Professor Valentin Flury, also at CPR, and other researchers across various institutes. Their collaboration not only proved their initial ideas but also uncovered a surprising dual role of Mrc1.
When DNA is copied during cell division, histones with their chemical tags must be transferred correctly to the new daughter DNA strands in order to be inherited to daughter cells. Mrc1 turns out to be a master regulator of this step in epigenetic inheritance, controlling the transmission of histones to the two new daughter strands. Mrc1 does this by binding histones alone and with another protein called Mcm2. This helps preserve the cell's memory of which genes to turn on or off.
Silencing of certain genes gets compromised
Their experiments revealed that mutations in Mrc1 disrupt the proper transfer of histones, leading to a loss of this crucial epigenetic information and affecting cell identity. When Mrc1 is mutated, the silencing of certain genes is compromised, which illustrates how important histones are in carrying and passing on epigenetic information.
This discovery has wide implications, as keeping the epigenetic landscape stable is essential for the proper functioning of all cells in the body. Problems with this process can lead to diseases like cancer and contribute to aging, where the epigenetic landscape deteriorates over time.
"I don't think we can estimate the full potential of our discovery yet, but we have revealed a very fundamental mechanism that maintains cell identity which, if it can be manipulated, could have significant implications for future medical research," concludes Valentin Flury.
