25 February 2025 Long-range enhancers found to be more sensitive to regulatory proteins than short-range enhancers Back to news Researchers of the De Laat group have discovered which proteins are of vital importance to regulating so-called long-range enhancer regulated genes. These are genes that are regulated by specialized pieces of DNA, called enhancers, that are distant from the gene that they regulate. This study, published in Cell Genomics on February 25th, demonstrates that genes that are regulated by long-range enhancers are much more sensitive to disturbances in the amount of regulatory proteins than genes that are regulated by short-range enhancers. Long-range enhancers often regulate genes that are only expressed in very specific cells, but also genes that play a large role in the development of cancer. By accounting for this new information about regulatory proteins and long-range enhancers, cancer medication could be improved in the future. The human body is made up of cells that all have the same DNA. DNA contains genesA small piece of DNA with a specific function. For example, genes determine which color our eyes have and whether we have curly or straight hair. In a human cell, the DNA contains about 30.000 genes, each having a specific function. Genes are hereditary and can therefore be passed on to offspring. that can be turned on or off. You can view DNA as a sort of recipe book. On the DNA are genes which you can see as recipes and when you use those recipes, you get proteins. Proteins are the building blocks of cells and execute many processes in the cell. Which genes are on and which are off in a cell determines, among others, the function, form and size of the cell. This is what determines the difference between a skin cell and a muscle cell for example. Enhancers as gene regulators Genes in humans are often regulated by enhancers. Enhancers are pieces of DNA that determine whether genes are turned on or off. Enhancers can be related to cooks who decide which recipes are and are not used. The greater the distance on the DNA between the enhancer and the gene, the more difficult it is for the enhancer to turn on the gene. This is comparable to recipes that a cook has in his standard repertoire (short distance between enhancer and gene) and recipes that he only uses on special occasions (long distance between enhancer and gene), like for example turkey for thanksgiving or Easter eggs for Easter. Why is regulating genes important? Long-distance enhancers are often used for genes that only need to be expressed under very specific circumstances. Think of genes that are necessary for very specialized cells and oncogenes. Oncogenes are genes that, when they are switched on too much, can cause cancer. This means that when oncogenes are not regulated properly, for example because their enhancer switches the gene on too much, this can lead to cancer. Enhancers are therefore regulated by so-called regulatory proteins. It was previously unknown whether long-range enhancers can be affected by other regulatory proteins than short-range enhancers. That is why the researchers of the De Laat group wanted to know if there are regulatory proteins that specifically affect long-range enhancers. Short-range enhancers do not need cohesion to turn on the gene, whereas long-range enhancers do. The enhancer and the gene are bent towards each other by cohesion. The gray line represents DNA. Green represents that the gene is on while red represents it is off. Credit: Sjoerd Tjalsma, Copyright: Hubrecht Institute Cohesin, mediator and other proteins “What we saw is that the regulatory proteins cohesion and mediator specifically affect long-range enhancers more than short-range enhancers” says Sjoerd Tjalsma, lead author of the study. “Cohesin makes DNA loop, which brings long-range enhancers closer to the gene they regulate by bending the pieces of DNA they are on,” says Tjalsma. “Because of this, the enhancer can switch on the gene better”. In a healthy cell that has the optimal amount of regulatory proteins, both short-range and long-range enhancers can switch on genes. In a diseased cell or the wrong cell type for the gene, short-range enhancers can switch on genes properly whereas long-range genes cannot. The gray line represents DNA. Green represents that the gene is on while red represents it is off. Credit: Sjoerd Tjalsma, Copyright: Hubrecht Institute Alongside cohesin and mediator, this study showed that long-range enhancers are more sensitive to regulatory proteins in general than short-range enhancers. “This means that long-range enhancers require perfect levels of regulatory proteins to switch on a gene,” says Tjalsma. This is comparable to a cook who uses recipes for special occasions only under those specific circumstances. Short-range enhancers, on the other hand, do not require perfect conditions and can switch on genes just fine with lower levels of regulatory proteins. Just like a cook who cooks on a regular weekday. Medical applications Tjalsma and colleagues research can lead to several applications in the future, such as for example cancer medication. Because oncogenes often depend on long-range enhancers, it would be theoretically be possible to moderate them by targeting regulatory proteins such as cohesin and mediator in medication. Another disease that could benefit from the knowledge gained from this research is sickle cell anemia. This is a hereditary disease that is caused by a genetic mistake and is lethal in many cases. Researchers of the De Laat group are currently conducting research that builds on the research of Tjalsma: by playing with the distance between enhancer and gene, it may be possible to develop a new therapy for sickle cell anemia treatment in the future. Publication Long-range enhancer-controlled genes are hyper-sensitive to regulatory factor perturbations. Sjoerd J.D. Tjalsma, Niels J. Rinzema, Marjon J.A.M. Verstegen, Michelle Robers, Andrea Nieto-Aliseda, Richard A. Gremmen, Amin Allahyar, Mauro J. Muraro, Peter H.L. Krijger, Wouter de Laat. Cell Genomics, 2025. Wouter de Laat is group leader at the Hubrecht Institute, professor of Biomedical Genomics at the UMC Utrecht and Investigator at Oncode Institute.
