title: A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator.
abstract: Production of functional proteins requires multiple steps, including gene transcription and posttranslational processing. MicroRNAs (miRNAs) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that miRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with an miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl(-) permeability independent of elevated mRNA levels. An miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, ΔF508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 and restored Cl(-) transport to cystic fibrosis airway epithelia. This miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process more broadly than recognized previously. This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.
authors.affiliation: Department of Pediatrics, Interdisciplinary Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Ostedgaard
authors.forename: Amy E
authors.initials: AE
authors.lastname: Walz
authors.forename: John T
authors.initials: JT
authors.lastname: Fisher
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: Kim A
authors.initials: KA
authors.lastname: Lennox
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Jacobi
authors.forename: Scott D
authors.initials: SD
authors.lastname: Rose
authors.forename: Mark A
authors.initials: MA
authors.lastname: Behlke
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
mesh_terms: D001692:Biological Transport; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis* / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: D002712:Chlorides; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D056264:Sin3 Histone Deacetylase and Corepressor Complex