title: MicroRNA-27b targets gremlin 1 to modulate fibrotic responses in pulmonary cells.
abstract: Fibrosis is a chronic disease characterized by an excessive deposition of scar tissue in the affected organs. A central mediator of this process is transforming growth factor-β (TGF-β), which stimulates the production of extracellular matrix proteins such as collagens. MicroRNAs (miRNAs) have been implicated in both fibrosis as well as in TGF-β signaling, but the extent of their regulation has not been fully defined. A functional screen was conducted using a library of miRNA inhibitors to identify miRNAs that affect TGF-β-induced type I collagen expression, a key event in the development of fibrosis. The inhibition of one miRNA in particular, miR-27b, caused a significant increase in type I collagen expression. We found that miR-27b directly targets Gremlin 1 by binding to its 3'-UTR, reducing its mRNA levels. TGF-β signaling decreased miR-27b expression and caused a corresponding increase in Gremlin 1 levels, suggesting that TGF-β regulates Gremlin 1 expression in part by modulating miR-27b expression. Reducing Gremlin 1 levels by either siRNA-mediated gene silencing or by using the miR-27b mimic inhibited the expression of several genes known to be involved in fibrosis, while increasing Gremlin 1 levels by the addition of either recombinant protein or the miR-27b inhibitor enhanced the expression of these genes. In summary, we have demonstrated that miR-27b targets Gremlin 1, and that this regulation likely represents an important control point in fibrotic pathways.
authors.affiliation: Inflammation and Remodeling Research Unit, Pfizer, Inc., Cambridge, Massachusetts, 02140.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Graham
authors.forename: Cara M M
authors.initials: CM
authors.lastname: Williams
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions; D002460:Cell Line; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; D024042:Collagen Type I; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta
keywords: CELL BIOLOGY; CELL SIGNALING; FIBROSIS; GENE EXPRESSION; GREMLIN 1; MicroRNA; TRANSFORMING GROWTH FACTOR BETA (TGFbeta)