Diabetes is a group of metabolic diseases that affects millions of people. Despite this, little is known about the underlying molecular mechanisms. Diabetes is characterised by an impaired blood-glucose regulation that can lead to severe consequences, such as kidney failure, and premature death. Pancreatic islets are one of the major tissues to understand diabetes pathogenesis as they produce insulin, a hormone central for blood-glucose homeostasis. Our previous work showed that studying epigenomic regulation is key to giving insight into the molecular mechanisms underlying diabetes, as risk-associated genomic variants are enriched at transcriptional regulatory regions named enhancers. To give further insight in pancreatic islet transcriptional regulation, I aimed to decipher the 3D chromatin organisation, an aspect of epigenomic regulation in human pancreatic islets that remained largely unexplored until now.
As part of my PhD project I have studied high-resolution chromatin interaction maps that characterise 3D chromatin organisation at different levels, from single interactions between specific pair of genomic loci to large genomic topological domains known as TADs. These high-resolution chromatin interaction maps, integrated with a large collection of epigenomic datasets, allowed me to describe several aspects of islet 3D chromatin organisation, such as the identification of islet-selective chromatin structures associated to islet-specific gene expression. Moreover, I identified groups of enhancers that gather in 3D space. These 3D enhancer clusters were frequently found in loci key for islet function and highly enriched in diabetes associated variants.
The results of this thesis allow us to have a more accurate picture of the epigenomic regulation in human pancreatic islets and how non-coding diabetes risk variants could be impairing enhancer-promoter communication.