Abstract
BackgroundRecent advances in the functional analyses of endogenous non-coding RNA (ncRNA) molecules, including long non-coding RNAs (LncRNAs), have provided a new perspective on the crucial roles of RNA in gene regulation. Consequently, LncRNA deregulation is a key factor in various diseases, including pulmonary disorders like Cystic Fibrosis (CF). CF is the most common life limiting recessive disease in the U.S., and is due to mutations in the CFTR gene. CF mutations, of which the most common is F508del-CFTR, prevents correct folding, trafficking and function of the mutant CFTR protein and is further manifested by the hyper-expression of pro-inflammatory cytokines and chemokines into the airway lumen leading to bronchiectasis and culminating in lung destruction.MethodsHere we report a distinct LncRNA signature and corresponding mRNAs that distinguishes CF lung (airway and parenchyma) tissues from matched non-CF controls (n = 4 each group), generated by microarray specific for LncRNAs which includes corresponding mRNA expressions. In silico analyses of the cellular processes that are impacted by these LncRNAs was performed using Gene Ontology (GO). A selected subset of LncRNAs were validated by quantitative real-time PCR.ResultsWe have identified 636 LncRNAs differentially expressed in CF airway epithelium and 1974 in CF lung parenchyma compared to matched non-CF controls (fold change ≥2, p < 0.05), majority of which (> 50%) are intergenic. Interestingly, 15 of these differentially expressed LncRNAs and 9 coding mRNAs are common to airway and parenchyma tissues. GO analyses indicates that signaling pathways and cell membrane functions are significantly affected by the alteration in LncRNA expressions in CF lung tissues. Seven of the differentially expressed LncRNAs, exhibit similar expression trends in CFBE41o- compared to control cells.ConclusionUnderstanding the mechanisms by which these LncRNAs regulate CF disease phenotype will help develop novel therapeutic targets for CF and related pulmonary diseases, such as COPD and Asthma.
Highlights
Cystic Fibrosis (CF) is the most common life limiting recessive disease in the U.S and is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene
long non-coding RNA (LncRNA) are classified according to their position relative to protein-coding genes, and are divided into five classes [5, 6]: (i) intronic LncRNAs are located within an intron of a proteincoding gene in either direction; (ii) long intergenic non-coding RNAs (ncRNAs) (LincRNA) are separated by transcriptional units from protein-coding genes; (iii) bidirectional LncRNAs are transcribed in opposite directions in relation to the promoter of a protein-coding gene; (iv) antisense LncRNAs are transcribed across the exons of protein-coding genes from the opposite direction; and (v) transcribed pseudogene LncRNAs are transcribed from a gene without the ability to produce a protein
LncRNA expression profiles in CF lung airway and parenchyma tissues To understand the role of LncRNAs in CF lung disease we performed comprehensive analyses of LncRNAs and corresponding mRNA expression profiles in lung tissues, both airway and parenchyma, obtained from CF patients undergoing lung transplant
Summary
Cystic Fibrosis (CF) is the most common life limiting recessive disease in the U.S and is due to mutations in the CFTR gene. Kumar et al Respiratory Research (2019) 20:284 have the ability to encode proteins, and they include all ncRNAs longer than 200 nucleotides (except rRNA and tRNA). These RNA molecules have provided a new perspective on the roles of RNAs in gene regulation [3, 4]. Recent advances in the functional analyses of endogenous non-coding RNA (ncRNA) molecules, including long non-coding RNAs (LncRNAs), have provided a new perspective on the crucial roles of RNA in gene regulation. CF mutations, of which the most common is F508del-CFTR, prevents correct folding, trafficking and function of the mutant CFTR protein and is further manifested by the hyper-expression of pro-inflammatory cytokines and chemokines into the airway lumen leading to bronchiectasis and culminating in lung destruction
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