Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression

Immunity. 2020 Feb 18;52(2):257-274.e11. doi: 10.1016/j.immuni.2020.01.003. Epub 2020 Feb 11.

Abstract

Genetics is a major determinant of susceptibility to autoimmune disorders. Here, we examined whether genome organization provides resilience or susceptibility to sequence variations, and how this would contribute to the molecular etiology of an autoimmune disease. We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.

Keywords: 3D genome organization; HiChIP; T cell development; chromatin; enhancers; epigenetics; genome folding; non-obese diabetes mouse; pancreas; type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor / metabolism
  • Chromatin / metabolism*
  • Chromosome Mapping
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / pathology
  • Epigenesis, Genetic
  • Gene Expression
  • Genetic Loci / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation
  • Genome / genetics
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Pancreas / pathology
  • Regulatory Sequences, Nucleic Acid
  • Thymocytes / pathology*

Substances

  • CCCTC-Binding Factor
  • Chromatin