ArticleImmunity2020
Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression.
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Article in Immunity, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44citing papers in PubMed
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44 citing papers in PubMed, 55 citations in OpenAlex.
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- Advancing Animal Models of Human Type 1 Diabetes.Cold Spring Harbor perspectives in medicine · 2024Review
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- Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity.Nature immunology · 2023Article
- Islet cells in human type 1 diabetes: from recent advances to novel therapies - a symposium-based roadmap for future research.The Journal of endocrinology · 2023Review
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- Three-dimensional genome organization in immune cell fate and function.Nature reviews. Immunology · 2023Review
- Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation.Nature immunology · 2023Article
- From thymus to tissues and tumors: A review of T-cell biology.The Journal of allergy and clinical immunology · 2023Review
- The Interplay of Transcription and Genome Topology Programs T Cell Development and Differentiation.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- 3D-Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma.Advanced genetics (Hoboken, N.J.) · 2022Article
- A novel diabetes typology: towards precision diabetology from pathogenesis to treatment.Diabetologia · 2022Review
- TCF-1 promotes chromatin interactions across topologically associating domains in T cell progenitors.Nature immunology · 2022Article
- Topologically associating domains are disrupted by evolutionary genome rearrangements forming species-specific enhancer connections in mice and humans.Cell reports · 2022Article
- Review
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Authors and funding
19 authors at 3 institutions in 1 country.
Maria FasolinoDepartment 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.
Naomi GoldmanDepartment 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.
Wenliang WangDepartment 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.
Benjamin CattauDepartment 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.
Yeqiao ZhouDepartment 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.
Jelena PetrovicDepartment 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.
Verena M LinkMetaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Allison CoteEpigenetics 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.
Aditi ChandraDepartment 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.
Michael SilvermanDepartment of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Eric F JoyceDepartment 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.
Shawn C LittleDepartment of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
HPAP ConsortiumThe Human Pancreas Analysis Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA, https://hpap.pmacs.upenn.edu/.
Klaus H KaestnerDepartment 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/.
Ali NajiInstitute 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.
Arjun RajEpigenetics 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.
Jorge Henao-MejiaInstitute 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.
Robert B FaryabiDepartment 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.
Golnaz VahediDepartment 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.
University of Pennsylvania · USCancer Research Institute · USNational Institutes of Health · US
Funding
VIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI DOUGLAS J EPSTEIN · 1986 to 2026
$48.3MPenn integrated Human Pancreas procurement and Analysis ProgramUC4DK112217 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI BETTS, MICHAEL R, FELDMAN, MICHAEL D · 2016 to 2020
$17.8MImmune System Development and RegulationT32AI055428 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI ALLMAN, DAVID M, OLIVER, PAULA MARIA · 2003 to 2025
$4.2MCritical role of TCF-1 on the epigenetic identity of memory T cellsR01HL145754 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI VAHEDI, GOLNAZ · 2019 to 2023
$2.3MNotch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast CancerR01CA230800 · NCI · UNIVERSITY OF PENNSYLVANIA · PI FARYABI, ROBERT BABAK · 2020 to 2025
$2.1MTransfer: Dissecting the interplay of MHC/HLA loci, the microbiota and autoimmune diabetesK08AI114970 · NIAID · CHILDREN'S HOSP OF PHILADELPHIA · PI SILVERMAN, MICHAEL A · 2015 to 2019
$893kNCI NIH HHS R01 CA230800NHLBI NIH HHS R01 HL145754NIAID NIH HHS K08 AI114970NIAID NIH HHS T32 AI055428NIDDK NIH HHS P30 DK019525NIDDK NIH HHS UC4 DK112217
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.
Indexed as
AnimalsCCCTC-Binding FactorChromatinChromosome MappingDiabetes Mellitus, Type 1Epigenesis, GeneticGene ExpressionGenetic LociGenetic Predisposition to DiseaseGenetic VariationGenomeHumansMiceMice, Inbred C57BLMice, Inbred NODPancreasCCCTC-Binding FactorChromatin3D genome organizationchromatinenhancersepigeneticsgenome foldingHiChIPnon-obese diabetes mousepancreasT cell developmenttype 1 diabetes
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