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

Animals CCCTC-Binding Factor / metabolism Chromatin / metabolism Chromosome Mapping Diabetes Mellitus, Type 1 / genetics 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
3D genome organization HiChIP T cell development chromatin enhancers epigenetics genome folding non-obese diabetes mouse pancreas type 1 diabetes

Journal

Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918

Informations de publication

Date de publication:
18 02 2020
Historique:
received: 07 06 2019
revised: 23 10 2019
accepted: 15 01 2020
pubmed: 13 2 2020
medline: 22 4 2020
entrez: 13 2 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.immuni.2020.01.003 PMID: 32049053 PMC: PMC7152927
pubmed: 32049053
pii: S1074-7613(20)30030-3
doi: 10.1016/j.immuni.2020.01.003
pmc: PMC7152927
mid: NIHMS1569049
pii:
doi:

Substances chimiques

CCCTC-Binding Factor 0
Chromatin 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

257-274.e11

Subventions

Organisme : NCI NIH HHS
ID : R01 CA230800
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK112217
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK019525
Pays : United States
Organisme : NIAID NIH HHS
ID : K08 AI114970
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145754
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI055428
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Maria Fasolino (M)

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.

Naomi Goldman (N)

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.

Wenliang Wang (W)

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.

Benjamin Cattau (B)

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.

Yeqiao Zhou (Y)

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.

Jelena Petrovic (J)

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.

Verena M Link (VM)

Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Allison Cote (A)

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.

Aditi Chandra (A)

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.

Michael Silverman (M)

Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Eric F Joyce (EF)

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.

Shawn C Little (SC)

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/.

Klaus H Kaestner (KH)

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/.

Ali Naji (A)

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.

Arjun Raj (A)

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.

Jorge Henao-Mejia (J)

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.

Robert B Faryabi (RB)

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.

Golnaz Vahedi (G)

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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Facteur de liaison à la séquence CCCTC › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Cartographie chromosomique › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Diabète de type 1 › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Système digestif › Pancréas › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Séquences d'acides nucléiques régulatrices › Genetic Variation in Type 1 Diabetes...
questionsmedicales.fr › Cellules › Thymocytes › Genetic Variation in Type 1 Diabetes...