Abstract
ObjectivesTo explore the long non-coding RNA (lncRNA) expression pattern of congenital lung malformations on a genome-wide scale and investigate their potential biological function in four subtypes of congenital lung malformations.MethodsWe obtained both lesions and normal lung control tissues from the patients diagnosed with CPAM-I, CPAM-II, ILS, and ILS-CPAM, and underwent lobectomy (i.e., surgical removal of the whole lobe which contains the localized lesion as well as normal lung tissue). Then, we performed lncRNA transcriptome profiling in these tissues by RNA sequencing (RNA-seq). A comprehensive bioinformatics analysis was conducted to characterize the expression profiles and relevant biological functions and for multiple comparisons of lncRNA expression in the different subtypes of congenital lung malformation tissues. Furthermore, the lncRNA-mRNA co-expression network was constructed, and dysregulated mRNAs were functionally analyzed. Finally, gene set enrichment analysis (GSEA) was used to predict the potential molecular mechanism of the identified lncRNAs.ResultsA total of 5921 lncRNA transcripts were identified between congenital lung malformations tissues and normal lung control tissues. Compared with normal lung control, 481of these expressed lncRNAs were upregulated and 142 were downregulated in CPAM-I, 91 were upregulated and 14 were downregulated in CPAM-II, 39 were upregulated and 38 were downregulated in ILS, and 201 were upregulated and 38 were downregulated in ILS-CPAM. Unsupervised clustering and principal component analysis of the expressed lncRNAs visualized the differences between normal lung control and different subtypes of congenital lung malformations samples. We also confirmed significant differences in the composition of differentially expressed genes (DEGs) and the differentially expressed lncRNAs (DE lncRNAs) between CPAM-I and other subtypes of congenital lung malformations, as well as in normal lung control tissues, and observed enrichment of DEGs in the regulation of the immune system, cell projection organization, and inflammatory pathways. Finally, we identified the lncRNA FLJ26850 might be related to congenital lung malformations via ZNF473.ConclusionsSignificant differences in lncRNAs expression patterns were observed between different subtypes of congenital lung malformations and normal control. The lncRNA FLJ26850 might be related to congenital lung malformations via ZNF473.
Highlights
Congenital lung malformations include a wide spectrum of developmental abnormalities involving large airways, pulmonary parenchyma, and blood vessels; congenital pulmonary airway malformations (CPAM, previously known as congenital cystic adenomatoid malformations [CCAM]), pulmonary sequestration, congenital lobar emphysema (CLE), and bronchogenic cysts are most commonly seen in clinics [1,2,3]
Genome‐wide profiling of the long non-coding RNA (lncRNA) expression associated with congenital lung malformations In the present study, we used a whole-genome RNA sequencing (RNA-seq) dataset recently generated from 15 samples containing three Congenital pulmonary airway malformations (CPAM)-I, three CPAM-II, three Intralobar sequestrations (ILS), three ILSCPAM lung tissue samples, and three normal lung control samples from patients undergoing surgical resection of congenital lung malformations
A subset of lncRNAs showed remarkable expression changes in different subtypes of congenital lung malformations compared to the normal lung control tissues, as shown in the Venn diagram, the bar plot, and the clustered heatmaps (Fig. 1a-c)
Summary
Congenital lung malformations include a wide spectrum of developmental abnormalities involving large airways, pulmonary parenchyma, and blood vessels; congenital pulmonary airway malformations (CPAM, previously known as congenital cystic adenomatoid malformations [CCAM]), pulmonary sequestration (further categorized into intralobar sequestrations [ILS] and extralobar sequestrations [ELS]), congenital lobar emphysema (CLE), and bronchogenic cysts are most commonly seen in clinics [1,2,3]. Given the increased risk of recurrent pneumonia and theoretical concern for malignant degeneration in later life, pediatric surgeons favor surgical removal of the affected lung in symptomatic infants [6]. Those lesions are grouped by cyst size (microcystic versus macrocystic) and origin of vascular supply (i.e., presence of an anomalous systemic arterial vessel [ILS or ELS], and pulmonary vs systemic venous drainage) regardless of their heterogeneous and complex nature [3, 7]. Considering the presence of hybrid lesions (such as CPAM with an anomalous systemic arterial vessel, known as ILS combined with CPAM), it is a long-held suggestion that congenital lung abnormalities are part of a continuum of developmental abnormalities instead of separate entities, but the exact etiology and molecular pathogenesis of congenital lung lesions remain unknown [3, 12]
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