Damage in the DNA inhibits transcription of genes by RNA polymerase II, which copies the genetic information of DNA into RNA. This impediment of RNA polymerase II results in severe cellular dysfunction and accelerated aging. Through a consortium combining unique complementary knowledge and expertise, we can study for the first time the causes and consequences of DNA damage from the perspective of a single molecule to that of a whole organism. Using this approach, we will study what exactly happens to RNA polymerase when encountering DNA damage, and directly link this to the consequences at the cellular and organism level.

MYC is a protein involved in regulating genes and is linked to 70% of all tumors. It can reprogram how a cell interprets its DNA, which can lead to cancer. This research focuses on understanding how MYC causes these changes in cells. Using innovative techniques like BANC-seq and CasTuner, the study investigates how the amount of MYC determines the outcomes of this reprogramming. The results will provide fundamental insights into how such proteins reprogram cells and help us better understand how cancer develops, paving the way for new treatment options.

In our bodies genes need to be activated at the right time and the right place. Many of these genes are activated by pieces of DNA that are located far away in the genome. The folding of our genome plays an important role in the correct regulation of these genes. We will investigate which factors are important in this process. This will lead to a better understanding how genes are regulated during embryonal development and what happens in developmental disorders.

The early mammalian epiblast consists of pluripotent cells that differentiate into three germ layers—ectoderm, mesoderm, and endoderm—during gastrulation. The mammalian epiblast is heterogeneous, with stochastic transcriptomic and epigenomic differences influencing their response to signals. Understanding how such stochastic cells make robust fate decisions is a major challenge requiring accessible models, live-cell imaging, single-cell multi-omics, and computational modeling. By combining “gastruloids,”, a mouse embryo-like structure generated from stem cells, with these technologies, our multidisciplinary team will define cellular states and trajectories to advance knowledge of lineage specification and regenerative medicine.

Stem cells are vital for our health. In the intestine, they maintain the organ, and allow it to heal after damage. Changes in these cells in the intestine are known to cause diseases including cancer and ulcerative colitis. In this proposal we will study these cells in order to understand how they make the proteins they need, and how this process is hijacked by disease. In doing this we can potentially identify ways to modify this, improving the health of the organ.