29 February 2024 Vici grants for Jop Kind and Puck Knipscheer Back to news Group leaders Jop Kind and Puck Knipscheer receive prestigious Vici grants from the Dutch Research Council (NWO). The grant will enable them to develop an innovative line of research and expand their research groups. Hubrecht Institute director Geert Kops says: “This is a wonderful recognition of the groundbreaking research that Puck and Jop have been doing on genome repair and gene expression in cells for years. We are very proud of the fact that they work in our Hubrecht team. The Vici grant will give them the opportunity to explore new paths, and we can’t wait to see the extraordinary discoveries they will make in the coming years.” Jop Kind: positioning and activity of genes during embryonic development The research of group leader Jop Kind is aimed at developing new techniques to study gene expression: the on-off switching of parts of DNA in the cell. Gene expression must be tightly regulated because it determines what a cell looks like and what it will do. Genes that are inactive, and therefore switched ‘off’, are often located at the edge of the cell nucleus. The cell probably prevents them from ending up in the middle, where pieces of DNA that should be ‘on’ are actively transcribed. This spatial separation between parts of the DNA can be found in the cells of many different animals, but the precise relationship between the positioning and activity of genes is still unknown. Read more With his Vici grant, Kind wants to gain more insight into this: “My research group previously developed several single cell techniques, which allow us to study gene expression in individual cells. The Vici grant offers us the opportunity to further develop these techniques. Our goal is to be able to take even more measurements simultaneously in one cell.” Specifically, the researchers want to look at three processes: the spatial localization of the DNA in the cell nucleus, how the DNA is packaged in a protein structure called chromatin, and gene activity. By determining all this simultaneously in many individual cells, and then arranging those cells in time, the researchers can determine what is cause and consequence. “It is a kind of molecular time machine: you determine what happens in the cell and then look back in time to see what preceded it. Do you see a piece of DNA first detach from the edge of the nucleus and does the gene become active only after that? Or do you already see activation when the DNA is still attached to the edge? This can tell us whether and how exactly the spatial localization of DNA contributes to switching genes on and off,” says Kind. In addition, the researchers also want to actively manipulate the positioning of the DNA. Kind: “We also want to develop a technique that enables us to anchor DNA to the edge of the cell nucleus, or to detach it from the edge, so that we can properly study the effects of this.” With his research, Kind wants to better understand how cells specialize during early embryonic development and ultimately form all tissues. His group will study this in different contexts, such as the specialization of embryonic cells into nerve cells, and the development of the limbs and brain. “And ultimately, there are always opportunities to apply our new techniques in all kinds of other areas,” Kind concludes. Read less Puck Knipscheer: DNA obstacles during replication Group leader Puck Knipscheer investigates DNA replication: the process of copying the DNA. This must occur before a cell divides to ensure that the new cells contain the same genetic information as the old one. With each division, a cell is faced with the enormous task of very precisely copying 3 billion base pairs, the letters of the DNA code. The protein factories responsible for replication regularly encounter obstacles along the way in the form of alternative DNA structures. Instead of the normal DNA structure, which is a double helix shape, these alternative structures are like knots in the strands. If this is not resolved, the protein factories will become stuck. This can cause all kinds of problems, such as mutations in the DNA. How the cell clears these obstacles remains largely unknown. Read more With her Vici grant, Knipscheer will further investigate these mechanisms: “We would like to know which proteins the cell has to solve alternative DNA structures and how that works exactly. We have recently studied a specific structure, the G-quadruplex structure, and discovered new mechanisms with which the cell can solve it. But this is probably just the tip of the iceberg.” The researchers therefore want to unravel this further. For this purpose, the group uses protein extracts from frog eggs. “These extracts contain just about everything that is in a cell, and especially many of the protein factories for DNA replication. We add DNA to these proteins, which is then copied. It is a biochemical system in a test tube, so no cells are involved,” Knipscheer explains. The researchers can introduce DNA with G-quadruplex structures into this system and can then determine which proteins are attracted from the extract to solve this problem. They also want to look at the consequences of such obstacles for the DNA. “We are going to sequence the DNA, meaning that we read the DNA code, to see whether the presence of the obstacle causes mutations in the DNA,” says Knipscheer. In addition to G-quadruplex structures, there are many other alternative DNA structures that Knipscheer also wants to understand better. Furthermore, the group would also like to investigate the regulation of these structures in living cells, and in the context of so-called repeat expansion diseases. In these diseases, alternative DNA structures cause problems during replication, among other things. “Thanks to the Vici grant, we can set up these new lines of research and develop new techniques. We hope to gain more insight into how all those proteins in the cell are constantly working to resolve unwanted DNA structures, so that replication does not go wrong and our genetic material remains intact.” Read less About the Vici grant The NWO Vici grant is intended for senior researchers who have proven that they are capable of developing their own line of research. With the funding they can continue and further develop their research. The maximum grant is 1.5 million euros. A total of 35 Vici grants were awarded this year. Jop Kind is group leader at the Hubrecht Institute, professor by special appointment of Single Cell Epigenomics at the Radboud University Nijmegen and Oncode Investigator. Puck Knipscheer is group leader at the Hubrecht Institute, professor by special appointment of Biochemistry of Genome maintenance at the Leiden University Medical Center and Oncode Investigator.
