A matter of distance – PhD defense Sjoerd Tjalsma

Our body is made up of cells of all shapes and sizes, performing a wide range of functions. For instance, nerve cells ensure communication in our brain, while intestinal cells absorb nutrients. Yet all these cells contain exactly the same information, stored in the form of genes on the DNA. Different cell types arise by switching the right genes on and off. From the enormous amount of information on the DNA, a nerve cell and an intestinal cell ‘choose’ a different set of instructions to carry out.

Genetic switches

For the body to function properly, it is important that the on-off switching of genes is accurately regulated. Here, an important role is played by enhancers: pieces of DNA that work as switches to turn on genes. Enhancers use proteins to do this. Sometimes enhancers are located right next to the gene they activate, but there can also be a large piece of DNA in between. The exact role of this difference in distance in the regulation of genes was not yet known. That is why Tjalsma wanted to investigate this in his PhD research.

Long distance relationship

His first question was how enhancer-gene distance affects the way enhancers regulate genes. To answer this question, he used cells in which he removed different proteins that are used by enhancers for gene activation. From this, he concluded that distant enhancers need more help from proteins to activate genes. An example is the cohesin complex: proteins that can fold the DNA. Enhancers that are close to their target gene can manage on their own and do not need cohesin.

When Tjalsma looked at proteins that are used by all enhancers, he saw that faraway enhancers need exactly the right amount of protein, while enhancers that are close by are not so sensitive to this. “The results show that the enhancer-gene distance contributes to genes only being activated under the perfect conditions, and for example not accidentally in the wrong cell type,” says Tjalsma.

A nearby enhancer

He then wondered why distant enhancers exist at all. What would happen if you brought them closer to their target genes? Tjalsma and his colleagues removed pieces of DNA in between enhancers and their genes to investigate this. They then looked at the effect on gene activation. “We saw that bringing an enhancer closer causes activation of genes that are normally switched off,” says Tjalsma. The researchers are the first to demonstrate this.

Ode to fundamental research

Tjalsma’s work teaches us more about how cells regulate which genes are on and off. The importance of this is very clear to him: “Personally, I find this kind of fundamental research very valuable. It creates a better understanding of the world in which we live. If scientists create a broad base of knowledge, new ideas can emerge to take original directions within science, to develop new technologies or to improve healthcare, for example,” he says.

Cancer and gene therapy

The new knowledge from Tjalsma’s PhD research can find various applications in the future. For example, it can contribute to understanding cancer, which often comes with disrupted gene regulation. “We know that oncogenes – certain genes that can contribute to the development of cancer – can have distant enhancers. Our research shows that in these types of genes, regulation needs to be very precise, but at the same time we know that if this goes wrong in oncogenes, the consequences can be serious,” Tjalsma explains.

In addition, bringing enhancers closer could be applied as gene therapy in the future. This seems particularly promising for the treatment of sickle cell disease and beta-thalassemia, since Tjalsma and his colleagues found a way to intervene in the globin genes, which are disrupted in these diseases. “This disruption is in one of the globin genes. Another globin gene, which is normally switched off, can be activated to compensate for the defect. We have succeeded in doing this by bringing enhancers closer,” says Tjalsma. The method could offer an alternative to the current gene therapy for these diseases, which is not yet used everywhere, is very expensive and works in a different way. “The more different ways we study to activate these genes, the greater the chance that we will succeed in curing these patients in the future.”

The PhD experience

Looking back, Tjalsma is positive about his PhD. At the same time, every PhD trajectory comes with difficulties and doubts. “It’s normal to have ups and downs,” says Tjalsma. “There will always be moments when you start questioning the relevance of your research and wonder whether it will ever be finished. For me it was good to realize that when something doesn’t work, it can bounce back. Some projects didn’t end up in my thesis, but I still learned a lot working on them. And when you’re in a difficult situation, seek out the things you know motivate you.”

For Tjalsma, an example of this was his first conference after the COVID-19 pandemic. “I remember really getting energized from everyone discussing their projects, providing feedback and talking about PhD life. This gave me perspective again on what I like about doing science.” He advises other PhD students to keep communicating honestly with their group leader and colleagues, and to seek support from others. In the end, Tjalsma looks back with satisfaction. “I am very happy with how my projects wrapped up.”