Transcriptomics

Dataset Information

3

A microRNA network regulates expression and biosynthesis of CFTR and CFTR-ΔF508.


ABSTRACT: Production of functional proteins requires multiple steps including gene transcription and post-translational processing. MicroRNAs (miRNA) 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 microRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with a miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl- permeability independently of elevated mRNA levels. A 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, 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 novel miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process broader than previously recognized. This discovery also provides new therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation. 12 samples of Calu-3 cells representing different interventions.

ORGANISM(S): Homo sapiens  

SUBMITTER: Shyam Ramachandran  

PROVIDER: E-GEOD-38956 | ArrayExpress | 2012-09-04

SECONDARY ACCESSION(S): GSE38956PRJNA169413

REPOSITORIES: GEO, ArrayExpress

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Publications

A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator.

Ramachandran Shyam S   Karp Philip H PH   Jiang Peng P   Ostedgaard Lynda S LS   Walz Amy E AE   Fisher John T JT   Keshavjee Shaf S   Lennox Kim A KA   Jacobi Ashley M AM   Rose Scott D SD   Behlke Mark A MA   Welsh Michael J MJ   Xing Yi Y   McCray Paul B PB  

Proceedings of the National Academy of Sciences of the United States of America 20120801 33


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 SIN3  ...[more]

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