Enzymatic barcode reader switches our genes on or off

Our bodies are composed of more than two hundred different types of cells that perform different jobs and form different organs, such as in the skin, blood or the brain. Although all cells have an identical set of genes, different cells express a different subset of them to gain unique identity and function. A Danish research group, in collaboration with international partners, has now uncovered the targets of key enzymes, called CBP and p300, that control which genes are switched on or off. 

“CBP and p300 are at the heart of the way by which cells mark genes that need to be turned on. The enzyme functions as a barcode writer that puts chemical marks on the genome to turn on specific genes that define cellular identity. We identified thousands of previously unknown marks and this new knowledge will be important for understanding how cell identity is established and how dysregulation of these enzymes results in diseases, such as cancer” explains the lead author of the study Professor Chuna Choudhary, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Catastrophic effects on the cell
Which genes are turned on is closely dictated by the surrounding environment, ensuring that only the right genes in the right cells are activated. Researchers have long known that CBP and p300 play an important role in these so-called epigenetic processes: how cells mark genes to turn them on and off. For nearly two decades, researchers have also known that these enzymes function by placing tiny acetyl groups on proteins that regulate genes.

“However, the identity of the proteins that are targeted by CBP and p300 has remained a mystery. The problem has been that there was no tool to inhibit CBP and p300. This means it was not previously possible to rapidly turn off their activities and to study their protein targets. So the only option available was to remove the enzyme completely. However, this takes a longer time and because the enzymes are so important, removing them has catastrophic effects on the cell, so this was not a good option,” says Dr. Brian Weinert, Associate Professor, another of the lead authors of the study.

A breakthrough came when one of their collaborators from USA identified specific inhibitors of CBP and p300 and contacted the Danish researchers from the University of Copenhagen who have world-leading expertise in discovering acetylation marks in cells. This collaboration between the international teams allowed the researchers to tackle this decades old problem.

“We knew that these enzymes regulate proteins by marking them with the acetyl groups, but we did not know where these marks were placed. However, with the new chemical and advanced protein sequencing technologies, we could see what happened when we decreased the activity of CBP/p300.” 

Treatment of cancer and developmental disabilities
The results were astounding, because they revealed that the CBP and p300 can acetylate not just a few, but thousands of acetylation marks in cell. The new discovery paves the way for numerous studies on the signalling pathways through which CBP/p300 regulates our genes. 

“We are investigating some of these regulators, but the scope of the findings is so huge that we anticipate that many other researchers will use our findings to further understand how CBP and p300 regulates different cellular functions. One of the main objective of our research is actually to make these new data available to the entire research community,” says Dr. Takeo Narita from Novo Nordisk Foundation Center for Protein Research, who is also one of the first authors of this study.

Interestingly, faults in CBP and p300 are linked to several human diseases, including cancer and developmental disorders, such as Rubinstein-Taybi Syndrome, which is characterized by severe developmental disabilities.

“We think that this new discovery is so important that it will benefit many basic research projects worldwide. Ultimately, this will benefit many people by generating new knowledge and discoveries that will help treat these diseases.”

“Time-resolved analysis reveals rapid dynamics and broad scope of the CBP/p300 acetylome” has been published in Cell. Chuna Choudhary is employed at the Novo Nordisk Foundation Centre for Protein Research, University of Copenhagen. The project was carried out in collaboration with researchers from the USA and the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Denmark.

Written by Morten Busch.

Contact
Prof. Chuna Choudhary
Email: chuna.choudhary@cpr.ku.dk 
Phone: 0045 24426643