3D-ADAPT · Analysis of tridimensional changes caused by type 2 Diabetes-Associated varianTs

Analysis of tridimensional changes caused by type 2 Diabetes-Associated varianTs

Type 2 diabetes (T2D) is a metabolic disorder that affects more than 400 million people worldwide. The prevalence of diabetes has doubled in the last 30 years becoming a serious global concern; however, the molecular mechanisms underlying this disease remain largely unknown. In practice, this means that patients with T2D are treated with drugs that try to lower their blood glucose, but do not affect the subjacent mechanisms, failing to affect the progression of the disease. Lack of molecular insight also prevents personalization of preventive or therapeutic interventions. T2D results from the interplay between genetic, environmental and behavioral factors, such as obesity and a sedentary lifestyle. Genetic studies carried out using large datasets of T2D patients and healthy control individuals have been able to identify genetic variants that predispose to T2D risk. Interestingly, most of these susceptibility sequences do not lie on genes (the DNA regions that code for proteins), but on non-coding segments. Non-coding regions comprise around 98% of the total of our DNA, and even though they were initially dismissed as “junk DNA”, we currently know that non-coding regions contain regulatory sequences that are responsible for the activation of genes in the right tissue and the right stage during our lifetime. Not only they are essential for the normal functioning of our body, but alterations in them have also been associated with several human disorders. Among non-coding regions, “enhancers” are regulatory elements that concentrate the highest frequency of variants that predispose to T2D. Some of these enhancers activate the expression of genes that are important for the function of insulin-producing beta cells in the pancreatic islets. Importantly, studies have shown that the presence of T2D-associated genetic variants within these enhancers can alter their function. However, in most cases, the variant-containing enhancers are very far away from their target genes in the DNA molecule, which hinders the identification of the gene that will ultimately be affecting beta-cell function. Recent advances in the field of 3D structure have shown that chromosomes are highly compacted and organized within the nucleus of each cell, which means that regions that might be very distant in the linear space are close in 3D via the formation of DNA loops. 3D methods will thus help us understand what genes the enhancers are contacting with. There is very limited information about 3D interactions of regulatory elements occurring in human pancreatic islets in health and in a disease condition such as T2D, therefore this project aimed at investigating the 3D chromatin structure of human islets and to use these 3D maps to identify gene targets of T2D-associated genetic variants.

Data: CORDIS, © European Union