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New study: How Proteins Control Genes to Prevent our Cells from Maldeveloping

If our cells would replicate 100% accurately when they need replacing, we would be without a wide range of diseases. However, they don’t; errors occur during replication, leading to illness. A new study takes us deep into the cell's machinery, where the genes in our DNA are regulated.

By Birgitte Svennevig, , 3/11/2024

Every time a cell in our body prepares to divide, an extremely complex process begins to ensure that the mother cell's DNA is copied into a new daughter cell along with all the correct instructions for which genes on the DNA strand should be turned off and which should be activated.

If errors occur in this process and the new cell is not identical to the mother cell, damages and disease may occur.

Researchers are therefore interested in learning more about these processes and why the copying of DNA and instructions sometimes goes wrong.

Constant DNA replication of the cell

All humans have a unique DNA strand, originating from a single cell: the fertilized egg cell, which has divided and created the billions of cells that make up the complete human being. They all contain a copy of the DNA strand created at fertilization. However, different cells decode the DNA in different ways, allowing for the formation of more than 200 different cell types. Some cell types die quickly and need to be replaced many times during life; for example, skin cells and intestinal cells are renewed every few days. Each time a new cell is created, a copy of the unique DNA strand is made for the new cell.

Two such researchers are Professor Ole Nørregaard Jensen and academic staff member Tina Ravnsborg from the Department of Biochemistry and Molecular Biology. They are co-authors of a new German-Danish-English-Dutch study led by researchers from the German research center Helmholtz Munich and published in the scientific journal Nature

With their study, the research team has provided new insights into how DNA and instructions are maintained and decoded in the cell. The instructions to the daughter cell are given by special chemical tags, which can either sit directly on the DNA or on structures around it in the cell nucleus. These chemical tags are also called epigenetic modifications.

In their study, the researchers have identified more than 2000 different proteins, all playing a role in this process.

May lead til uncontrolled cell growth

- Our study shows how epigenetic modifications are interpreted and decoded by recruiting specific proteins to precise locations in the DNA. This activates selected genes, such as those ensuring that the cell and its daughter cells remain for example liver cells and do not develop into cancer cells. Epigenetic modifications thus give the cell a memory, so it remembers which genes to turn on and which to turn off, both before and after cell division. If errors occur in these epigenetic mechanisms, the wrong genes may be turned on, leading to uncontrolled cell growth and thus cancer, says Ole Nørregaard Jensen.

The process of maintaining DNA and the cell's instructions for how individual genes should be used during cell division is extremely complex. Not only does the entire DNA strand, present in every cell nucleus, need to be copied.

The epigenetic modifications ensuring that specific parts of the DNA's genes are activated while others are inactivated must also be copied to the new cell, giving the new cell an exact recipe for whether it should grow into a liver cell, a skin cell, or another type of cell.

The two meters long DNA strand

Epigenetic modifications can either sit directly on the DNA or on the structures responsible for packing the DNA strand in the cell nucleus. The DNA strand itself is 2 meters long and must be efficiently packed in the cell nucleus; it is coiled around some proteins called histones.

These epigenetic modifications are the focus of the new study. The more than 2000 proteins identified by the research team all play a role in how histones read and decode the mother cell's DNA and how histones copy this information and pass it on to the new cell.

- We see that very small changes in the epigenetic modifications in histones lead to the recruitment of different protein complexes, which then initiate a reprogramming of the cell, says Ole Nørregaard Jensen, continuing:

Factors like environment, age and hormones are at play

- I dare say that we have in fact decoded part of the language of proteins and gained insight into how this language is interpreted and remembered inside the cells.

Epigenetic modifications can be caused by many factors: environment, nutritional status, age, hormones, and lifestyle in general.

Ole Nørregaard Jensen and Tina Ravnsborg have contributed to the study by performing protein analyses with mass spectrometry. This analytical method is called proteomics, and with SDU's advanced equipment, the researchers have been able to find previously unseen molecular details in how the DNA in a cell is regulated.

The research team has decided to make its results and tools available to others via the website MARCS - Modification Atlas of Regulation by Chromatin States. 

Meet the researcher

Ole Nørregaard Jensen is a professor and head of research at the Department of Biochemistry and Molecular Biology. One of his research fields is the role of proteins in disease development. His research is supported by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Ministry of Higher Education and Science. He heads the research infrastructure INTEGRA, where mass spectrometry is used for protein analysis.

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Editing was completed: 11.03.2024