Thesis Defense Corina Markodimitraki: A tale of two measurements

The human body consists of trillions of cells that come in all shapes and sizes. They are the building blocks of the body, cooperating with each other to form a fully functioning organism. There are 200 different types of cells in the human body, all with different functions and appearances. Yet, they all contain the same genetic information: the same DNA. How can the same DNA code result in different outcomes? To quote Markodimitraki: “It is all about exposure.” 

Blueprint

Not all DNA is available for the cell to read and act upon at all times: the parts of the DNA that are exposed differ between cell types. Some parts of the DNA are tightly packed, while other parts are looser and therefore easier to read. In other words, the DNA is folded differently. The way DNA is folded is determined by the interactions between the DNA and certain types of proteins located in the core – or nucleus – of the cell.

When the cell reads the DNA, it replicates the code. This creates so-called messenger RNA (mRNA) transcripts. The cell uses these transcripts as a blueprint for producing proteins. Every type of cell needs different kinds of proteins and therefore the parts of the DNA that are replicated into mRNA differ per cell. Researchers determine the type of cell they are looking at by measuring the mRNA transcripts.

New technique

Until now, a technique to directly study the relationship between the folding of DNA and the production of mRNA was lacking. During her PhD, Markodimitraki and her colleagues filled this technical gap by developing a technique that measures both protein-DNA interactions and mRNA transcripts in the same cell. This technique called scDam&T-seq allowed them to accurately study how the packing of DNA in a cell influences the production of mRNA.

Flexible DNA

Cells store DNA in their nucleus. The DNA in the core of the nucleus is more flexible and open and therefore easier to read, whereas the DNA in the outer regions of the nucleus is more tightly packed. With their newly developed technique, Markodimitraki and her colleagues confirmed a long-standing hypothesis: cells do not read the DNA that is located in the outer regions of the cell’s nucleus. Therefore, these DNA regions are not copied into mRNA, nor are they translated into proteins. Rather, the DNA packed at the core of the nucleus mostly determines what types of proteins are produced.

Technical solutions

Markodimitraki and her colleagues also used the technique to study DNA folding in the brain of developing mice. With her thesis, Markodimitraki presents a technique that is therefore highly valuable for studying the relationship between DNA folding and mRNA production in both cells in the lab as well as in living animals. Markodimitraki: “My thesis presents technical solutions in the field of DNA architecture.”