PhD Defense by Jan F. Nickels

Title: Spatiotemporal dynamics of nucleosome-mediated epigenetic gene silencing

How is H3K9me-based repressive heterochromatin established and maintained? Our first study used single-cell experiments and mathematical modeling to understand how this process unfolds in space and time at fission yeast's mating-type region. We discovered that heterochromatin formation is an exponential process with a rate inversely proportional to the size of the genomic region. Mathematical modeling explains this mechanistically if deacetylation or methylation at H3K9 occurs as a long-range positive feedback reaction. Furthermore, we found that the absence of binding sites for the DNA-binding protein Atf1 slows the process enormously. The second study theoretically explores how small bistable epigenetic regions maintain their integrity within euchromatin. We show that heterochromatin-mediated negative feedback and both local and long-range positive feedback enable effective confinement of these regions. Finally, the third study examines the impact of the H3.3(K36M) mutation, frequently found in chondroblastomas and other types of cancer, on epigenetic memory. The mutation disrupts epigenetic memory, and a mathematical model incorporating KRAB-mediated nucleation and the cooperation of H3K9me3, H3K36 methylation, and DNA methylation predicts a disrupted epigenetic landscape. These studies shed light on the intricate dynamics and underlying mechanisms of epigenetic regulation, providing valuable insights into this fascinating field.