Differential epigenome-wide DNA methylation patterns in childhood obesity-associated asthma

While DNA methylation plays a role in T-helper (Th) cell maturation, its potential dysregulation in the non-atopic Th1-polarized systemic inflammation observed in obesity-associated asthma is unknown. We studied DNA methylation epigenome-wide in peripheral blood mononuclear cells (PBMCs) from 8 obese asthmatic pre-adolescent children and compared it to methylation in PBMCs from 8 children with asthma alone, obesity alone and healthy controls. Differentially methylated loci implicated certain biologically relevant molecules and pathways. PBMCs from obese asthmatic children had distinctive DNA methylation patterns, with decreased promoter methylation of CCL5, IL2RA and TBX21, genes encoding proteins linked with Th1 polarization, and increased promoter methylation of FCER2, a low-affinity receptor for IgE, and of TGFB1, inhibitor of Th cell activation. T-cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These findings suggest that dysregulated DNA methylation is associated with non-atopic inflammation observed in pediatric obesity-associated asthma.

[1]  M. Levings,et al.  The Role of the PI3K Signaling Pathway in CD4+ T Cell Differentiation and Function , 2012, Front. Immun..

[2]  Stefan Rose-John,et al.  ADAM17: a molecular switch to control inflammation and tissue regeneration. , 2011, Trends in immunology.

[3]  A. Weinmann,et al.  Molecular mechanisms by which T‐bet regulates T‐helper cell commitment , 2010, Immunological reviews.

[4]  D. Ferguson,et al.  DNA Double-Strand Break Repair: A Relentless Hunt Uncovers New Prey , 2006, Cell.

[5]  J. Greally,et al.  Optimized design and data analysis of tag-based cytosine methylation assays , 2010, Genome Biology.

[6]  J. Greally,et al.  DNA methylation profiling using HpaII tiny fragment enrichment by ligation-mediated PCR (HELP). , 2010, Methods.

[7]  K. Asano,et al.  Role of prostaglandin D(2) and its receptors in the pathophysiology of asthma. , 2008, Allergology international : official journal of the Japanese Society of Allergology.

[8]  Nam-Hee Kwon,et al.  DNA Methylation and the Expression of IL-4 and IFN-γ Promoter Genes in Patients with Bronchial Asthma , 2008, Journal of Clinical Immunology.

[9]  G. Diette,et al.  The impact of self‐identified race on epidemiologic studies of gene expression , 2011, Genetic epidemiology.

[10]  D. Dockery,et al.  Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III , 2001, Thorax.

[11]  S. Ho,et al.  Environmental epigenetics and asthma: current concepts and call for studies. , 2008, American journal of respiratory and critical care medicine.

[12]  Xue F. Huang,et al.  CCL5 as an adjuvant for cancer immunotherapy , 2010, Expert opinion on biological therapy.

[13]  Helene Myrtue Nielsen,et al.  DNA methylation based biomarkers: practical considerations and applications. , 2012, Biochimie.

[14]  M. Daly,et al.  Methods for high-density admixture mapping of disease genes. , 2004, American journal of human genetics.

[15]  J. Lang,et al.  Body Mass Index-Percentile and Diagnostic Accuracy of Childhood Asthma , 2009, The Journal of asthma : official journal of the Association for the Care of Asthma.

[16]  Anita Preininger,et al.  Insights into G protein structure, function, and regulation. , 2003, Endocrine reviews.

[17]  D. Krewski,et al.  Does leptin play a role in obesity–asthma relationship? , 2009, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[18]  Third Expert Panel on theDiagnosis,et al.  Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma , 1997 .

[19]  K. Clément,et al.  Defining macrophage phenotype and function in adipose tissue. , 2011, Trends in immunology.

[20]  J. Douwes,et al.  Body Mass Index and Childhood Asthma: A Linear Association? , 2008, The Journal of asthma : official journal of the Association for the Care of Asthma.

[21]  D. Solé,et al.  Obesity and Its Relationship with Asthma Prevalence and Severity in Adolescents from Southern Brazil , 2006, The Journal of asthma : official journal of the Association for the Care of Asthma.

[22]  D. Schwartz,et al.  Genomic medicine and lung diseases. , 2012, American journal of respiratory and critical care medicine.

[23]  H. Shin,et al.  Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy , 2013, BMC Medical Genetics.

[24]  P. Sly,et al.  CpG methylation patterns in the IFNγ promoter in naive T cells: Variations during Th1 and Th2 differentiation and between atopics and non‐atopics , 2006, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[25]  R. Peled,et al.  The Relationship Between Asthma and Obesity in Children: Is It Real or a Case of Over Diagnosis? , 2004, The Journal of asthma : official journal of the Association for the Care of Asthma.

[26]  A. Dixon,et al.  Relationship of Adipokines with Immune Response and Lung Function in Obese Asthmatic and Non-Asthmatic Women , 2011, The Journal of asthma : official journal of the Association for the Care of Asthma.

[27]  M. Croft,et al.  TNF superfamily in inflammatory disease: translating basic insights. , 2012, Trends in immunology.

[28]  F. Milagro,et al.  Individuality and epigenetics in obesity , 2009, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[29]  W. Leonard,et al.  Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. , 2013, Immunity.

[30]  A. Ferrante,et al.  Obesity‐induced inflammation: a metabolic dialogue in the language of inflammation , 2007, Journal of internal medicine.

[31]  LIF-Dependent Signaling: New Pieces in the Lego , 2011, Stem Cell Reviews and Reports.

[32]  马建新,et al.  用FEV6.0代替FVC诊断气道阻塞和肺功能受限[英]/Swanney MP…∥Am J Respir Crit Care Med. , 2002 .

[33]  A. Ginde,et al.  Body mass index and acute asthma severity among children presenting to the emergency department , 2009, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[34]  S. Johnston,et al.  Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD4+ and CD8+ T cells in atopic asthma. , 2005, American journal of respiratory and critical care medicine.

[35]  D. Vignali,et al.  How regulatory T cells work , 2008, Nature Reviews Immunology.

[36]  John M Greally,et al.  Automated computational analysis of genome-wide DNA methylation profiling data from HELP-tagging assays. , 2012, Methods in molecular biology.

[37]  V. Sánchez-Margalet,et al.  Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. , 2001, Cellular immunology.

[38]  Sin-Ho Jung,et al.  Alveolar macrophages from overweight/obese subjects with asthma demonstrate a proinflammatory phenotype. , 2012, American journal of respiratory and critical care medicine.

[39]  E. Crain,et al.  Do obese inner-city children with asthma have more symptoms than nonobese children with asthma? , 2000, Pediatrics.

[40]  Reid F. Thompson,et al.  Cytosine Methylation Dysregulation in Neonates Following Intrauterine Growth Restriction , 2010, PloS one.

[41]  B. Ozanne,et al.  CD23/FcεRII: molecular multi‐tasking , 2010, Clinical and experimental immunology.

[42]  S. Weiland,et al.  Associations of adipokines with asthma, rhinoconjunctivitis, and eczema in German schoolchildren , 2009, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[43]  R. Rangel,et al.  PRELI, the human homologue of the avian px19, is expressed by germinal center B lymphocytes. , 2000, International immunology.

[44]  J. Celedón,et al.  An official American Thoracic Society Workshop report: obesity and asthma. , 2010, Proceedings of the American Thoracic Society.

[45]  F. Pixley,et al.  CSF-1 signaling in macrophages: pleiotrophy through phosphotyrosine-based signaling pathways , 2012, Critical reviews in clinical laboratory sciences.

[46]  P. Georgel,et al.  CHD proteins: a diverse family with strong ties. , 2007, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[47]  J. Greally,et al.  Epigenetic changes in B lymphocytes associated with house dust mite allergic asthma , 2011, Epigenetics.

[48]  Suneet Agarwal,et al.  Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. , 1998, Immunity.

[49]  P. Gluckman,et al.  Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective , 2008, International Journal of Obesity.

[50]  Farshid S. Garmaroudi,et al.  DNA Methylation Profiles of Airway Epithelial Cells and PBMCs from Healthy, Atopic and Asthmatic Children , 2012, PloS one.

[51]  V. Kuchroo,et al.  Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cells. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[52]  David E Levy,et al.  IFNgamma signaling-does it mean JAK-STAT? , 2008, Cytokine & growth factor reviews.

[53]  M. Nalls,et al.  Admixture mapping of white cell count: genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies. , 2008, American journal of human genetics.

[54]  Nam-Hee Kwon,et al.  DNA methylation and the expression of IL-4 and IFN-gamma promoter genes in patients with bronchial asthma. , 2008, Journal of clinical immunology.

[55]  Robert Barouki,et al.  The aryl hydrocarbon receptor system , 2012, Drug metabolism and drug interactions.

[56]  R. Arens,et al.  Obesity-associated asthma in children: a distinct entity. , 2012, Chest.

[57]  S. Chinn,et al.  Association between obesity and asthma in 4-11 year old children in the UK. , 2001, Thorax.