Global hypomethylation in childhood asthma identified by genome-wide DNA-methylation sequencing preferentially affects enhancer regions.

Autor: Thürmann L; Associated Member of the German Center for Lung Research, Unit for Molecular Epidemiology, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Klös M; Associated Member of the German Center for Lung Research, Unit for Molecular Epidemiology, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Mackowiak SD; Associated Member of the German Center for Lung Research, Center for Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Bieg M; Associated Member of the German Center for Lung Research, Center for Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Bauer T; German Cancer Research Center (DKFZ), Division of Theoretical Bioinformatics and Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Heidelberg, Germany., Ishaque N; Associated Member of the German Center for Lung Research, Center for Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Messingschlager M; Associated Member of the German Center for Lung Research, Unit for Molecular Epidemiology, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Herrmann C; Health Data Science Unit, Heidelberg University Hospital, Heidelberg, Germany., Röder S; Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Bauer M; Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Schäuble S; Friedrich-Schiller-University Jena, Jena University Language & Information Engineering (JULIE) Lab, Jena, Germany.; Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Systems Biology and Bioinformatics Unit, Jena, Germany., Faessler E; Friedrich-Schiller-University Jena, Jena University Language & Information Engineering (JULIE) Lab, Jena, Germany., Hahn U; Friedrich-Schiller-University Jena, Jena University Language & Information Engineering (JULIE) Lab, Jena, Germany., Weichenhan D; Division of Cancer Epigenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Mücke O; Division of Cancer Epigenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Plass C; Division of Cancer Epigenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Center for Lung Research (DZL), Heidelberg, Munich, Germany., Borte M; Children's Hospital, Municipal Hospital 'St. Georg', Leipzig, Germany., von Mutius E; German Center for Lung Research (DZL), Heidelberg, Munich, Germany.; Dr. von Hauner Children's Hospital, Ludwig Maximilian University Munich, Munich, Germany.; Helmholtz Zentrum München-German Research Center for Environmental Health, Institute for Asthma and Allergy Prevention, Neuherberg, Germany., Stangl GI; Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, Halle (Saale), Germany., Lauener R; Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland., Karvonen AM; Department of Health Security, Finnish Institute for Health and Welfare, Kuopio, Finland., Divaret-Chauveau A; Pediatric Allergy Department, Children's Hospital, University Hospital of Nancy, Vandoeuvre les Nancy, France.; UMR 6249 Chrono-Environment, Centre National de la Recherche Scientifique and University of Franche-Comté, Besançon, France.; EA3450 Development, Adaptation and Handicap, University of Lorraine, Nancy, France., Riedler J; Children's Hospital, Schwarzach, Austria., Heinrich J; German Center for Lung Research (DZL), Heidelberg, Munich, Germany.; Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU, Munich, Germany.; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany., Standl M; German Center for Lung Research (DZL), Heidelberg, Munich, Germany.; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany., von Berg A; Department of Pediatrics, Research Institute, Marien-Hospital Wesel, Wesel, Germany., Schaaf B; Pediatric Outpatient Department, Bad Honnef, Germany., Herberth G; Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Kabesch M; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany., Eils R; Associated Member of the German Center for Lung Research, Center for Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.; Health Data Science Unit, Heidelberg University Hospital, Heidelberg, Germany.; German Center for Lung Research (DZL), Heidelberg, Munich, Germany., Trump S; Associated Member of the German Center for Lung Research, Unit for Molecular Epidemiology, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Lehmann I; Associated Member of the German Center for Lung Research, Unit for Molecular Epidemiology, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.; German Center for Lung Research (DZL), Heidelberg, Munich, Germany.
Jazyk: angličtina
Zdroj: Allergy [Allergy] 2023 Jun; Vol. 78 (6), pp. 1489-1506. Date of Electronic Publication: 2023 Feb 10.
DOI: 10.1111/all.15658
Abstrakt: Background: Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.
Methods: Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.
Results: In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.
Conclusion: This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.
(© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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