DNA Methylation in Nasal Epithelium: Strengths and Limitations of an Emergent Biomarker for Childhood Asthma

Solazzo, G.; Ferrante, Giuliana; Grutta, Stefania La

doi:10.3389/fped.2020.00256

Cited by 11 publications

(5 citation statements)

References 36 publications

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“…48 Nevertheless, accumulating evidence indicates that the nasal epithelium is a biologically relevant proxy for the lower airway epithelium in asthma and is better biomarkers for asthma prediction. 14,15,47 Several studies, 10,14,15,30,49 consistent with our previous studies, 11,12 identified significant DNAm differences in nasal epithelium between asthmatic and nonasthmatic children.…”

Section: Discussionsupporting

confidence: 86%

“…Recent studies showed that the methylation patterns of peripheral blood mononuclear cells and airway epithelial cells were not well correlated in asthma 14,47 and other lung diseases 48 . Nevertheless, accumulating evidence indicates that the nasal epithelium is a biologically relevant proxy for the lower airway epithelium in asthma and is better biomarkers for asthma prediction 14,15,47 . Several studies, 10,14,15,30,49 consistent with our previous studies, 11,12 identified significant DNAm differences in nasal epithelium between asthmatic and nonasthmatic children.…”

Section: Discussionsupporting

confidence: 75%

“…Additionally, DNAm is highly tissue‐ and cell‐type specific. Recent studies showed that the methylation patterns of peripheral blood mononuclear cells and airway epithelial cells were not well correlated in asthma 14,47 and other lung diseases 48 . Nevertheless, accumulating evidence indicates that the nasal epithelium is a biologically relevant proxy for the lower airway epithelium in asthma and is better biomarkers for asthma prediction 14,15,47 .…”

Section: Discussionmentioning

confidence: 99%

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Nasal DNA methylation differentiates severe from non‐severe asthma in African‐American children

Zhu¹,

Zhang

Rothenberg

et al. 2020

Allergy

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Background: Asthma is highly heterogeneous, and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis.This study aimed to identify nasal epithelial DNAm differences between severe and nonsevere asthmatic children and evaluate the impact of environmental exposures.Methods: Thirty-three nonsevere and 22 severe asthmatic African American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. Twenty-seven DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs was altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched.Conclusions: Significant differences in nasal epithelial DNAm were observed between nonsevere and severe asthma in African American children, a subset of which may be useful to predict disease severity. These CpG sites are subjected to the influences of environmental exposures and may regulate gene expression. | 1837 ZHU et al.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Nasal DNA methylation differentiates severe from non‐severe asthma in African‐American children

Zhu¹,

Zhang

Rothenberg

et al. 2020

Allergy

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“…However, the role of other novel biomarkers indicated in this study have to be confirmed in the future. Subsequent studies confirmed the important role of DNA methylation in the development of childhood asthma, as well as the potential to use the nasal epithelium as a source to identify early biomarkers for asthma [119]. Some of the genes harboring CpGs or other differentially methylated DNA sequences are related to epithelial cell function, epithelium integrity, and extracellular matrix remodeling, including: GJA4 (Gap junction protein alpha 4), POSTIN (Periostin), LDLRAD3 (low density lipoprotein receptor class A domain containing 3), ATP9B (Atpase Phospholipid transporting 9B), LAMA5 (Laminin subunit alpha 5), PDE6A (Phosphodiesterase 6A), NOS1AP(Nitric iodide synthase 1 adaptor protein), and KCNH2 (Potassium voltage-gated channel subfamily H member 2) [120][121][122][123].…”

Section: Parental Asthma the Environment Epigenetics And The Epitheliummentioning

confidence: 86%

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

Fang

Roth

2021

JPM

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Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood.

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“…Changes in DNA methylation in respiratory epithelia have been implicated in several inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis and idiopathic pulmonary fibrosis [ 54 , 55 , 56 ]. Knowledge of a potential role of epithelial DNA methylation modifications in the host response to respiratory pathogens is highly limited.…”

Section: Discussionmentioning

confidence: 99%

Bronchial epithelial DNA methyltransferase 3b dampens pulmonary immune responses during Pseudomonas aeruginosa infection

et al. 2021

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DNA methyltransferase (Dnmt)3b mediates de novo DNA methylation and modulation of Dnmt3b in respiratory epithelial cells has been shown to affect the expression of multiple genes. Respiratory epithelial cells provide a first line of defense against pulmonary pathogens and play a crucial role in the immune response during pneumonia caused by Pseudomonas (P.) aeruginosa, a gram-negative bacterium that expresses flagellin as an important virulence factor. We here sought to determine the role of Dntm3b in respiratory epithelial cells in immune responses elicited by P. aeruginosa. DNMT3B expression was reduced in human bronchial epithelial (BEAS-2B) cells as well as in primary human and mouse bronchial epithelial cells grown in air liquid interface upon exposure to P. aeruginosa (PAK). Dnmt3b deficient human bronchial epithelial (BEAS-2B) cells produced more CXCL1, CXCL8 and CCL20 than control cells when stimulated with PAK, flagellin-deficient PAK (PAKflic) or flagellin. Dnmt3b deficiency reduced DNA methylation at exon 1 of CXCL1 and enhanced NF-ĸB p65 binding to the CXCL1 promoter. Mice with bronchial epithelial Dntm3b deficiency showed increased Cxcl1 mRNA expression in bronchial epithelium and CXCL1 protein release in the airways during pneumonia caused by PAK, which was associated with enhanced neutrophil recruitment and accelerated bacterial clearance; bronchial epithelial Dnmt3b deficiency did not modify responses during pneumonia caused by PAKflic or Klebsiella pneumoniae (an un-flagellated gram-negative bacterium). Dnmt3b deficiency in type II alveolar epithelial cells did not affect mouse pulmonary defense against PAK infection. These results suggest that bronchial epithelial Dnmt3b impairs host defense during Pseudomonas induced pneumonia, at least in part, by dampening mucosal responses to flagellin.

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DNA Methylation in Nasal Epithelium: Strengths and Limitations of an Emergent Biomarker for Childhood Asthma

Cited by 11 publications

References 36 publications

Nasal DNA methylation differentiates severe from non‐severe asthma in African‐American children

Nasal DNA methylation differentiates severe from non‐severe asthma in African‐American children

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

Bronchial epithelial DNA methyltransferase 3b dampens pulmonary immune responses during Pseudomonas aeruginosa infection

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