Characterization of genome-wide chromatin accessibility in airway basal cells derived from patients with Tracheobronchopathia Osteochondroplastica (TO)
The assay for transposase-accessible chromatin using sequencing (ATAC-Seq) was applied to investigate the TO-associated chromatin alteration(s) appeared in tracheobronchial basal cells (TBBC). ATAC-Seq data was generated on cultured TBBCs derived from lesion regions and patient-matched lesion-free regions of two patients with Stage I and Stage III disease respectively, in parallel with control TBBCs from two normal donors. Six samples were spontaneously divided into two main groups (TO and non-TO) based on both differentiation phenotype and clustering results. The relationship between chromatin accessibility and future gene expression during basal stem cell differentiation was analyzed in combination with RNA-Seq. We identified 222914 increased chromatin accessible regions whilst 6406 decreased chromatin accessible regions in TO cells compared to non-TO cells. Among 641 loci with TO-related increased accessibility at the promoter region, 22 were associated with up-regulated gene expression (cutoff at fold change>2, p<0.05), and out of which, 18 exhibited enhanced transcriptional induction during basal cell differentiation. On the other hand, there were 459 loci with decreased accessibility at the promoter region in TO, among which, 107 were associated with down-regulated expression (cutoff at fold change<-2, p<0.05) and 58/107 exhibited transcriptional suppression during differentiation. Our study suggests that chromatin remodeling may provide an explanation for the sustained basal cell malfunction in TO pathogenesis. Overall design: The landscape of altered chromatin accessibility in TO-derived tracheobronchial basal cells was explored by ATAC-Seq, in biological triplicate, compared to Non-TO basal cells derived from normal airway tissues.