Inflammatory bowel disease (IBD) affects millions of people worldwide. The incidence and the prevalence are rising every year. This chronic disease not only decreases patient's quality of life but also creates a huge socio-economic burden for society. For establishment of a curative therapy, it is critical to understand the pathophysiology of IBD and this requires comprehensive understanding of intestinal epithelial regeneration process at the molecular level. The immune system and the epithelial tissues co-orchestrate the process of epithelial repair, and defects in each part can result in the onset of IBD via delayed wound-healing of the epithelium. Whereas epithelial stem cells are essential for the normal maintenance of the colon, my preliminary evidence from murine colitis models suggests that a wide range of epithelial cells contribute to tissue repair by acquiring stem cell properties during the early phases of epithelial regeneration. As genome wide epigenetic modifications have significant impact on cellular identity, I speculate that the observed cellular plasticity involves significant changes in the epigenetic status and that epigenetic modifiers orchestrate intestinal epithelial regeneration. My aim is to understand the relationship between epithelial regeneration and the epigenetic landscape as well as to find the connection between the disarrangements of this system and the onset of IBD. I will address these questions using grafting and primary culture technologies that I developed during my Ph.D. This, combined with lineage tracing methods and techniques for assessing the epigenome, which are available at the host lab, form the fundamental platform for this proposal. This project will potentially reveal the integral mechanisms of intestinal epithelial repair following damage, the pathophysiological impact of epigenetic modifiers in IBD, and provide a new framework for assessing the aetiology and the onset of IBD.