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Abstract
Human respiratory conditions are largely influenced by the individual’s sex resulting in overall higher risk for males. Sex-based respiratory differences are present at birth suggesting a strong genetic component. Our objective was to characterize early life sex-based genomic signatures determined by variable X-chromosome methylation in the airways. We compared male versus female genome-wide DNA methylation in nasal airway samples from newborns and infants aged 1–6 months (N = 12). We analyzed methylation signals across CpG sites mapped to each X-linked gene using an unsupervised classifier (principal components) followed by an internal evaluation and an exhaustive cross-validation. Results were validated in an independent population of children (N = 72) following the same algorithm. X-linked genes with significant sex-based differential methylation in the nasal airway of infants represented only about 50% of the unique protein coding transcripts. X-linked genes without significant sex-based differential methylation included genes with evidence of escaping X-inactivation and female-biased airway expression. These genes showed similar methylation patterns in males and females suggesting unbalanced X-chromosome dosage. In conclusion, we identified that the human airways have already sex-based DNA methylation signatures at birth. These early airway epigenomic marks may determine sex-based respiratory phenotypes and overall predisposition to develop respiratory disorders later in life.
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1 Pontificia Universidad Javeriana, Department of Electronics Engineering, Bogota, Colombia (GRID:grid.41312.35) (ISNI:0000 0001 1033 6040)
2 Children’s National Medical Center, Division of Pulmonary and Sleep Medicine, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); George Washington University School of Medicine and Health Sciences, Department of Pediatrics, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510); Children’s National Medical Center, Center for Genetic Medicine, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
3 Children’s National Medical Center, Division of Neonatology, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
4 Johns Hopkins University School of Medicine, Division of Pediatric Allergy Immunology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
5 Yale University School of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New-Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)