Characterizing the impact of somatic mutations in immune and epithelial cell communication in ulcerative colitis

Somatic mutations have recently been linked to inflammatory bowel diseases. However, it remains unclear to what extent and through which mechanisms these mutations contribute to disease progression and alter the interaction between immune cells and intestinal epithelial cells. We aim to address these questions using a novel single-cell and single-strand DNA sequencing technology (Strand-seq) that we have recently developed to identify structural variant mutations at the cellular level and explore their molecular consequences at the clonal level. By integrating our innovative single-cell technologies with intestinal organoid models, we will investigate the full spectrum of somatic mutations arising in primary intestinal epithelia as well as in the T lymphocyte compartment of patients with ulcerative colitis (UC). Through this multi-omic analysis, we aim to characterize the somatic mutational landscape of UC tissues in order to define the types, frequencies, and molecular phenotypes of genetic subclones emerging during intestinal inflammation. We will then study the mechanisms of emergence and clonal expansion that shape somatic mutations in each tissue compartment to identify genetic drivers and molecular signatures that reflect disease status.