Abstract
Cystic fibrosis (CF) is a life-shortening genetic disease. The root cause of CF is heritable recessive mutations that affect the cystic fibrosis transmembrance conductance regulator (CFTR) gene and the subsequent expression and activity of encoded ion channels at the cell surface. We show that CFTR is regulated transcriptionally by the actions of a novel long noncoding RNA (lncRNA), designated as BGas, that emanates from intron 11 of the CFTR gene and is expressed in the antisense orientation relative to the protein coding sense strand. We find that BGas functions in concert with several proteins including HMGA1, HMGB1, and WIBG to modulate the local chromatin and DNA architecture of intron 11 of the CFTR gene and thereby affects transcription. Suppression of BGas or its associated proteins results in a gain of both CFTR expression and chloride ion function. The observations described here highlight a previously underappreciated mechanism of transcriptional control and suggest that BGas may serve as a therapeutic target for specifically activating expression of CFTR.
Highlights
Cystic fibrosis (CF) is an autosomal recessive disease that arises as a result of defects in the CF transmembrane conductance regulator (CFTR) gene[1,2,3] that encodes an ion channel in the apical membrane of epithelial cells
Some antisense long noncoding RNA (lncRNA) have been observed to function as endogenous regulators of epigenetic and transcriptional states of homology containing protein-coding genes
The data presented here suggest that the CFTR-associated antisense lncRNA BGas is www.moleculartherapy.org vol 24 no. 8 aug. 2016
Summary
Cystic fibrosis (CF) is an autosomal recessive disease that arises as a result of defects in the CF transmembrane conductance regulator (CFTR) gene[1,2,3] that encodes an ion channel in the apical membrane of epithelial cells. Genome-wide association analysis identified five modifier genes that contributed to lung disease in CF patients.[6] In addition, epigenetics has been shown to be a contributing factor in CF disease variability.[7] The regulatory mechanisms governing CFTR expression are complex and are still not entirely understood. It is evident, that histone modifications and DNA methylation may play a role in CFTR expression, suggesting an epigenetic component to CFTR transcriptional regulation. Histone deacetylase (HDAC) inhibitors have been shown to partially restore the DeltaF508 mutant phenotype in human primary airway epithelia, which signifies the potential for epigenetic therapies.[8,9]
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