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.

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.

The genetic information in our genome is organized into varying architectures of epigenetic states in different cell types. The exact function of these domains in the regulation of gene expression is poorly understood. Our proposal aims at better understanding the influence of local chromatin environment on gene expression specially promoter activity. Using high-throughput methods including a novel technology we will investigate alterations in transcription activity of a group of promoters when integrated at thousands of different locations in the genome serving as sensors of local chromatin influence on transcription. This will generate a detailed description of how different genetic (DNA regulatory elements) and epigenetic configurations interact with each other in the nucleus. Next, we aim to study the functional effects of epigenetic inhibitors on this interaction. Additionally, we will study how dynamics of transcription activation are regulated by local chromatin context and how transcription activation at one locus affects the adjacent genes. Altogether, our proposal has the potential to unravel the functional significance of different chromatin states and to provide the mechanistic details of how epigenetic drugs of medical significance influence chromatin in a functional manner.

Cracking the TCR code with scalable molecular tools We aim to better understand how the immune system can recognize disease by examining the interactions between T cell receptors (TCRs) and disease-associated antigens. These interactions are currently hard to study at scale. We will develop tools that allow high-throughput screening to identify TCR-antigen binding pairs. We will then train an artificial intelligence model to predict immune interactions. This project will extend our toolbox to gain critical knowledge about our immune system, paving the way for engineering T cell therapies, vaccines, and diagnostic tools.

Genomic instability is a major driving force in the development of cancer. While genomic instability can have lethal consequences through the loss of essential genes, it increases the probability that cells acquire the multiple genetic alterations required for cancer to develop. Efforts to uncover the underlying mechanisms driving genomic instability in cancer have revealed a prominent role for telomeres. Telomeres are highly specialized, complex structures of DNA, RNA and proteins that cap chromosome ends and protect them from being recognized as DNA double-strand breaks. Loss of telomere protection leads to activation of DNA damage checkpoints and processing of deprotected chromosome ends by DNA repair factors that lead to chromosome-end fusions and dicentric chromosomes. If such cells with fused chromosomes continue to divide, this results in breakage-fusion-bridge cycles and complex, unbalanced chromosome rearrangements. However, the precise mechanisms by which dysfunctional telomeres lead to chromosomal instability and cancer are largely unknown. Using candidate-driven and genome-wide screening approaches, we have recently set out to identify the factors that play an important role in telomere-driven genome instability. One of the telomere-induced genome instability regulators we identified is WHSC1, also known as MMSET or NSD2. Alterations in WHSC1 are strongly associated with the Wolf-Hirschhorn malformation syndrome (WHS) and with multiple forms of cancer, especially multiple myeloma. In this proposal we will mechanistically investigate how WHSC1 controls telomere-driven genomic instability and whether this function might contribute to its role in cancer development. In addition, we will address the intriguing possibility that WHSC1 affects telomere maintenance.