miR-29 Is a Major Regulator of Genes Associated with Pulmonary Fibrosis

Abstract

MicroRNAs (miRNA) are small regulatory RNAs that control gene expression by translational suppression and destabilization of target mRNAs. There is increasing evidence that miRNAs regulate genes associated with fibrosis in organs, such as the heart, kidney, liver, and the lung. In a large-scale screening for miRNAs potentially involved in bleomycin-induced fibrosis, we found expression of miR-29 family members significantly reduced in fibrotic lungs. Analysis of normal lungs showed the presence of miR-29 in subsets of interstitial cells of the alveolar wall, pleura, and at the entrance of the alveolar duct, known sites of pulmonary fibrosis. miR-29 levels inversely correlated with the expression levels of profibrotic target genes and the severity of the fibrosis. To study the impact of miR-29 down-regulation in the lung interstitium, we characterized gene expression profiles of human fetal lung fibroblast IMR-90 cells in which endogenous miR-29 was knocked down. This confirmed the derepression of reported miR-29 targets, including several collagens, but also revealed up-regulation of a large number of previously unrecognized extracellular matrix-associated and remodeling genes. Moreover, we found that miR-29 is suppressed by transforming growth factor (TGF)-β1 in these cells, and that many fibrosis-associated genes up-regulated by TGF-β1 are derepressed by miR-29 knockdown. Interestingly, a comparison of TGF-β1 and miR-29 targets revealed that miR-29 controls an additional subset of fibrosis-related genes, including laminins and integrins, independent of TGF-β1. Together, these strongly suggest a role of miR-29 in the pathogenesis of pulmonary fibrosis. miR-29 may be a potential new therapeutic target for this disease.

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

“…miR-29s are important regulators of cell-matrix adhesion 44,45 , and our data extend the role of these miRNAs to the control of cell-cell adhesion. By combining in silico and microarray analyses, we identified at least 4,707 mRNAs that are expressed in the skin and are potentially regulated by miR-29 through binding to their 3 0 UTRs.…”

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

“…45 Further, miR-155 and miR-29 were shown to be significantly increased after bleomycin injury and important in fibroblast survival. 45,46 miR-155 was shown to regulate keratinocyte growth factor (KGF; FGF7), resulting in reduced expression. 45 KGF is known to play a protective role in pulmonary fibrosis.…”

MicroRNA Expression Profile of Spleen CD4+ T Cells from Thioredoxin Primed Lung Transplanted Rats

“…Excessive and prolonged IL-1β generation is known to be associated with multiple acute and chronic inflammatory diseases in general (23,24) and specifically in clinically significant primary graft dysfunction in lung transplant patients (25). Similarly, down-regulation on miRNAs (miR-29 and miR-210) is associated in the modulation of pulmonary fibrosis (26,27). This is particularly significant in context with Trx-mediated increased expression of miR-146a suggesting suppressive role in acute and/or chronic inflammatory responses or down-regulation of miR-29 and miR-210 in inhibition of fibrosis in post-transplant graft injury and rejection.…”