Altered DNA folding may be at the heart of diseases with no known genetic causes

In order to compactly fit into our cells, DNA has to be folded. The folding allows linearly distant elements like enhancers to come close to their target genes in 3D space. This contact subsequently facilitates target gene transcription. Second-year PhD student Iwan Vaandrager and his colleagues at the Hubrecht Institute are investigating how changes in DNA folding may contribute to diseases by inducing widespread gene expression changes.

One part of the project focuses on genetic mutations that are linked to heart disease, but which are located in stretches of DNA without a known function, also known as non-coding DNA. Using data obtained from patient hearts, Iwan studies the 3D shape of these regions to understand how they contribute to disease development by regulating gene expression. The insights gained from this study will not only benefit research into heart disease, but also set a precedent for research into other conditions. Iwan states that “in many pathologies, we don’t have a clear genetic cause yet. With studies like this, we can functionalize the non-coding regions of DNA and understand what brings about a disease”.

In a second project, Iwan is trying to better understand how DNA folding is coordinated by structural proteins. In particular, he is interested in observing the consequences of recruiting these structural proteins to specific genomic locations, as he expects local changes in DNA folding and gene expression. This research is important because changes in DNA folding are theorized to play a role in various diseases.

With studies like this, we can functionalize the non-coding regions of DNA and understand what brings about a disease.

Current research already shows that disturbances of DNA folding can affect an organism’s health. Particularly in embryonic development, the consequences can be easily visualized, because “if DNA folding is off, flies develop multiple eyes or their wings are malformed. There is a clear relevance between DNA folding and something going wrong”. With this example in mind, Iwan speculates that by clarifying the mechanisms behind DNA folding his team could open the door to a new way of understanding diseases with widespread genetic changes that previously may have seemed random.

Iwan’s work is primarily computational, as he also completed a Master’s in “Bioinformatics and Systems Biology”. While doing his Bachelor’s in an interdisciplinary program at Amsterdam University College, he became fascinated with studying epigenetics as “the framework that translates physics to biology”. Now he hopes to contribute to epigenetic research himself by exploring the mechanism of DNA folding and its role in human health.