Regulatory DNA and Stem Cells in Complex Genetic Diseases

Abstract

Delineating the pathogenesis of complex genetic diseases is complicated by the great variety of genetic loci, genes, cell types, environmental factors and tissues that are involved. The genetic background of complex genetic diseases has been intensively studied through genome wide association studies (GWASs). This led to the association of many genetic loci to a multitude of diseases. The identification of causal variants and affected genes has proven difficult, thereby leaving some pathogenic mechanismsunresolved and potential therapeutic targets unrevealed. In this thesis, we study the involvement of DNA regulatory elements (DRE) in the pathogeneses of complex genetic diseases and epithelial mechanisms that are potentially involved in inflammatory bowel disease (IBD). In the first part of this thesis we studied loci associated to IBD, CVD cardiovascular diseases) and CKD (chronic kidney disease). We show that disease associated loci are enriched for active DRE and we used chromatin conformation capture to study the 3D configuration of these loci. Through this approach we identified many novel candidate genes, pathways and key regulators of IBD, CVD and CKD.Genetic studies on IBD have shown that the intestinal epithelium plays a important role in the pathogenesis of this complex genetic disease. Therefore, in the second part of this thesis, we use human intestinal organoids to study the interaction between bacterial antigens and the intestinal epithelium. We show that intestinal stem cells are a major source of the inflammatory response and that the responsiveness of the epithelium is regulated at the post-transcriptional level.