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

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Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression.
Immunity ( IF 25.5 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.immuni.2020.01.003
Maria Fasolino ₁ , Naomi Goldman ₁ , Wenliang Wang ₁ , Benjamin Cattau ₁ , Yeqiao Zhou ₂ , Jelena Petrovic ₂ , Verena M Link ₃ , Allison Cote ₄ , Aditi Chandra ₁ , Michael Silverman ₅ , Eric F Joyce ₆ , Shawn C Little ₇ , ₈ , Klaus H Kaestner ₉ , Ali Naji ₁₀ , Arjun Raj ₄ , Jorge Henao-Mejia ₁₁ , Robert B Faryabi ₂ , Golnaz Vahedi ₁₂

Affiliation

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.
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.
Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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.
Department of Cell and Developmental Biology, 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 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/.
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.
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.
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/.

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.

中文翻译：

1型糖尿病的遗传变异重新配置了T细胞的3D染色质组织并改变了基因表达。

遗传学是自身免疫性疾病易感性的主要决定因素。在这里，我们检查了基因组组织是否对序列变异提供了适应力或敏感性，以及这将如何促进自身免疫性疾病的分子病因学。我们在NOD小鼠，1型糖尿病（T1D）模型和抗糖尿病C57BL / 6小鼠的胸腺细胞中生成了线性和3D基因组组织的高分辨率图。多基因相互作用在基因组区域形成，该基因组区域包含在两种菌株的T细胞发育中具有突出作用的基因。但是，赋予糖尿病风险的基因座在NOD中合并了增强子和启动子，但在C57BL / 6胸腺细胞中却没有。NODxC57BL / 6 F1胸腺细胞的3D基因组图谱显示，NOD小鼠的基因组错折叠是顺式介导的。此外，用T1D浸润人类胰腺的免疫细胞显示出位于小鼠错误折叠的基因座上的基因表达增加。因此，遗传变异会导致3D染色质结构的改变以及基因表达的相关变化，这可能是自身免疫病理学的基础。

更新日期：2020-02-11

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