TWIST1 DNA methylation is a cell marker of airway and parenchymal lung fibroblasts that are differentially methylated in
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RESEARCH
Open Access
TWIST1 DNA methylation is a cell marker of airway and parenchymal lung fibroblasts that are differentially methylated in asthma Rachel L. Clifford1,3* , Chen Xi Yang2, Nick Fishbane2, Jamie Patel1, Julia L. MacIsaac3, Lisa M. McEwen3, Sean T. May4, Marcos Castellanos-Uribe4, Parameswaran Nair5, Ma’en Obeidat2,6, Michael S. Kobor3, Alan J. Knox1 and Tillie-Louise Hackett2,6
Abstract Background: Mesenchymal fibroblasts are ubiquitous cells that maintain the extracellular matrix of organs. Within the lung, airway and parenchymal fibroblasts are crucial for lung development and are altered with disease, but it has been difficult to understand their roles due to the lack of distinct molecular markers. We studied genome-wide DNA methylation and gene expression in airway and parenchymal lung fibroblasts from healthy and asthmatic donors, to identify a robust cell marker and to determine if these cells are molecularly distinct in asthma. Results: Airway (N = 8) and parenchymal (N = 15) lung fibroblasts from healthy individuals differed in the expression of 158 genes, and DNA methylation of 3936 CpGs (Bonferroni adjusted p value < 0.05). Differential DNA methylation between cell types was associated with differential expression of 42 genes, but no single DNA methylation CpG feature (location, effect size, number) defined the interaction. Replication of gene expression and DNA methylation in a second cohort identified TWIST1 gene expression, DNA methylation and protein expression as a cell marker of airway and parenchymal lung fibroblasts, with DNA methylation having 100% predictive discriminatory power. DNA methylation was differentially altered in parenchymal (112 regions) and airway fibroblasts (17 regions) with asthmatic status, with no overlap between regions. Conclusions: Differential methylation of TWIST1 is a robust cell marker of airway and parenchymal lung fibroblasts. Airway and parenchymal fibroblast DNA methylation are differentially altered in individuals with asthma, and the role of both cell types should be considered in the pathogenesis of asthma. Keywords: DNA methylation, Gene expression, Cell marker, Lung, Fibroblast, Airway, Parenchyma, Asthma
* Correspondence: [email protected] 1 Nottingham NIHR Biomedical Research Centre, Nottingham MRC Molecular Pathology Node, Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham, UK 3 BC Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes
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