How cells activate and deactivate genes

Disease and treatment 11. may 2021 3 min Professor Chuna Choudhary Written by Kristian Sjøgren

A new discovery changes the understanding of how cells regulate which genes are activated and deactivated.

Researchers have always believed that the cells use a molecular pause mechanism to deactivate genes and release the pause button to quickly activate them. However, new Danish research shows that this is not the case and that genetics textbooks need to be rewritten.

In addition to a pause mechanism, the cells have a system that recruits the molecular machines to translate DNA into functional proteins and a mechanism to start the machine when required.

“This discovery helps us to understand how specific genes are activated and deactivated at the right times in either fetal development or in response to internal or external environmental factors. All researchers in this field have focused on one specific mechanism of gene regulation, and we are now revising this,” explains a researcher behind the discovery, Chuna Choudhary, Professor and Group Leader, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The research has been published in Molecular Cell.

Your cells only use half your genes

All animals are complex beings that need to precisely control expression of their genes.

This applies during fetal development, in which the genes in some stem cells must be activated or deactivated to develop them into heart cells, liver cells, kidney cells or other cells.

This also applies when the cells have to respond to the changing environment, such as when the body has an infection. Then the cells have to make proteins to fight the infection, requiring the activation of many genes.

Each of your cells contains 20,000 genes, but only 10,000 of them are used by all types of cells. They are called the housekeeping genes, and all cells must use them to maintain basic cellular function.

The other cell type–specific genes remain present in the DNA but are only used by some specific cells or at specific times in life.

“The cells have developed ways to activate and deactivate specific genes, so that they are only active when they are needed. We now have a much better understanding of this mechanism for activating and deactivating genes,” says Chuna Choudhary.

Proteins are essential for regulating genes

Chuna Choudhary collaborated with colleagues from Denmark, Germany and Japan to use stem cells from mice to study the mechanism for activating and deactivating genes.

Mice, humans and all other animals have the same cellular mechanisms that regulate gene expression through epigenetics.

One such protein is p300/CBP, which is only present in complex organisms and not in bacteria and fungi.

p300/CBP is required for activating various genes during fetal development but not for regulating the housekeeping genes.

“We did not really understand previously how p300/CBP works and how quickly it activates and deactivates the genes,” explains Chuna Choudhary.

p300/CBP can deactivate genes in 5 minutes

To elucidate this essential cellular function, Chuna Choudhary and his collaborators previously mapped the molecular structure of p300/CBP and then identified a chemical that inhibits its function.

By inhibiting p300/CBP, the researchers revealed how it works and how quickly it can activate and deactivate genes when required.

“Having a chemical that can deactivate a protein very quickly enabled us to study the on-off switch of the genes much more precisely than previously possible. We found that deactivating p300/CBP deactivates the genes in less than 5 minutes,” says Chuna Choudhary.

Changes the understanding of how genes are activated and deactivated

The recent discovery, which Chuna Choudhary refers to as the big news, is how genes are regulated.

Polymerases are required to translate a gene into a protein. They do this by translating DNA into messenger RNA, which is then translated into a protein.

Researchers thought that the polymerases were placed on to the DNA in a kind of pause position. p300/CBP can subsequently come and activate the polymerases and thereby also relevant genes when required.

However, the new research results show that p300/CBP first recruits the polymerase on to the genes and then facilitates the release of the pause button. Both of these functions are important for gene activation.

Chuna Choudhary compares this with watching a video requiring that the TV be on and the pause button not be pressed.

If the TV is not on or the pause button is pressed, nothing happens.

“Previously, we only focused on the pause button and overlooked that the gene or TV must first be turned on. This study showed that the pause function remains , but recruiting polymerase is the most critical before the genes can be expressed. The big discovery is that now we can rapidly and selectively deactivate genes, and differentiate between the button that turns on the gene and the pause button,” explains Chuna Choudhary.

Enhancers are activated by p300/CBP activity–dependent PIC assembly, RNAPII recruitment, and pause release” has been published in Molecular 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 Germany and Japan and scientists from the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen. 

We are interested in obtaining novel understanding of the regulatory mechanisms in cell signaling. In particular, we are interested in unraveling the...

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