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Immunity. 2020 Feb 6. pii: S1074-7613(20)30030-3. doi: 10.1016/j.immuni.2020.01.003. [Epub ahead of print]

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

Author information

1
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
3
Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
4
Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
6
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
7
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
8
The Human Pancreas Analysis Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA, https://hpap.pmacs.upenn.edu/.
9
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Human Pancreas Analysis Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA, https://hpap.pmacs.upenn.edu/.
10
Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Human Pancreas Analysis Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA, https://hpap.pmacs.upenn.edu/; Department of Surgery, University of Pennsylvania Perelman, School of Medicine, Philadelphia, PA 19104, USA.
11
Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
12
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Human Pancreas Analysis Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA, https://hpap.pmacs.upenn.edu/. Electronic address: vahedi@pennmedicine.upenn.edu.

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

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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