Role of microRNAs in lung development and pulmonary diseases

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Abstract

MicroRNAs (miRNAs) are a class of small noncoding RNA which exert post-transcriptional gene regulation activity by targeting messenger RNAs. miRNAs have been found to be involved in various fundamental biological processes and deregulation of miRNAs is known to result in pathological conditions. In this review, we provide an overview of recent discoveries on the role played by this class of molecules in lung development and in pulmonary diseases, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease, and pulmonary artery hypertension. Considering the relevant role of these miRNAs under physiological and pathological conditions, they represent new clinical targets as well as diagnostic and prognostic tools. Therefore, this review pays special attention to recent advances and possible future directions for the use of miRNAs for clinical applications.

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Most cited references 148

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miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

Kimberly Cordes, Neil T. Sheehy, Mark White … (2009)

SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

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SMAD proteins control DROSHA-mediated microRNA maturation.

Brandi Davis, Aaron C Hilyard, Giorgio Lagna … (2008)

MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signalling pathways.

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RNA polymerase III transcribes human microRNAs.

Glen Borchert, William P. Lanier, Beverly Davidson (2006)

Prior work demonstrates that mammalian microRNA (miRNA or miR) expression requires RNA polymerase II (Pol II). However, the transcriptional requirements of many miRNAs remain untested. Our genomic analysis of miRNAs in the human chromosome 19 miRNA cluster (C19MC) revealed that they are interspersed among Alu repeats. Because Alu transcription occurs through RNA Pol III recruitment, and we found that Alu elements upstream of C19MC miRNAs retain sequences important for Pol III activity, we tested the promoter requirements of C19MC miRNAs. Chromatin immunoprecipitation and cell-free transcription assays showed that Pol III, but not Pol II, is associated with miRNA genomic sequence and sufficient for transcription. Moreover, the mature miRNA sequences of approximately 50 additional human miRNAs lie within Alu and other known repetitive elements. These findings extend the current view of miRNA origins and the transcriptional machinery driving their expression.

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Author and article information

Journal

Journal ID (nlm-ta): Pulm Circ

Journal ID (iso-abbrev): Pulm Circ

Journal ID (publisher-id): PC

Title: Pulmonary Circulation

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 2045-8932

ISSN (Electronic): 2045-8940

Publication date (Print): Apr-Jun 2013

Volume: 3

Issue: 2

Pages: 315-328

Affiliations

[1]Cardiovascular research institute, University of California San Francisco, CA 94158, USA

Author notes

Address for correspondence: Dr. Akiko Hata, Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd. South, Room 252T, San Francisco, CA 94158, Fax: 514-415-1173 E-mail: akiko.hata@ 123456ucsf.edu

Article

Publisher ID: PC-3-315

DOI: 10.4103/2045-8932.114758

PMC ID: 3757825

PubMed ID: 24015331

SO-VID: 72975b8b-2782-43aa-8603-754a64fefe8b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Role of microRNAs in lung development and pulmonary diseases

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Biomarkers for Inflammatory Lung Disease

Most cited references 148

miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

SMAD proteins control DROSHA-mediated microRNA maturation.

RNA polymerase III transcribes human microRNAs.

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