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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