Title: Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression
Author: Maria Fasolino, Naomi Goldman, Wenliang Wang, Benjamin Cattau, Yeqiao Zhou, Jelena Petrovic, Verena M. Link, Allison Cote, Aditi Chandra, Michael Silverman, Eric F. Joyce, Shawn C. Little, Klaus H. Kaestner, Ali Naji, Arjun Raj, Jorge Henao-Mejia, Robert B. Faryabi, Golnaz Vahedi
Issue&Volume: February 11, 2020
Abstract: Genetics is a major determinant of susceptibility to autoimmune disorders. Here, weexamined whether genome organization provides resilience or susceptibility to sequencevariations, and how this would contribute to the molecular etiology of an autoimmunedisease. We generated high-resolution maps of linear and 3D genome organization inthymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistantC57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring geneswith prominent roles in T cell development in both strains. However, diabetes risk-conferringloci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genomemapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD miceis mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increasedexpression of genes located on misfolded loci in mice. Thus, genetic variation leadsto altered 3D chromatin architecture and associated changes in gene expression thatmay underlie autoimmune pathology.