Genetic Variations in Type 1 Diabetes Reconfigure the 3D Chromatin Organization of T Cells [HiChIP-seq]

Despite overwhelming evidence supporting the role of genetics in susceptibility tocomplex diseases, such as autoimmune disorders, a fundamental unresolved questionis whether large numbers of sequence variants with small effect sizes can alter thespatial genome organization. Here, we provide the first report on the reconfiguration ofthe 3D genome due to nucleotide differences associated with type 1 diabetes, anautoimmune disorder. We show that the chromatin organization at T cell identity genesis identical between diabetes-susceptible and diabetes-resistant mouse strains despitethousands of sequence polymorphisms, suggesting that these loci are epigeneticallyresilient to genetic variation. However, molecular and optical mapping of genomefolding demonstrate that diabetes risk-conferring loci coalesce into close spatialproximity in T cells of diabetes-susceptible mice, forming regulatory cliques, andresulting in aberrant gene expression. Our data uncover 3D chromatin architecture asa new dimension in understanding complex diseases HiChIP was performed as described (Mumbach et al., 2016) using antibody against Smc1 (Bethyl, cat# A300-055A)