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MicroRNAs in inflammatory lung disease--master regulators or target practice?

Oglesby IK, McElvaney NG, Greene CM - Respir. Res. (2010)

Bottom Line: Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders.Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered.Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief.

View Article: PubMed Central - HTML - PubMed

Affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

ABSTRACT
MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs with immense significance in numerous biological processes. When aberrantly expressed miRNAs have been shown to play a role in the pathogenesis of several disease states. Extensive research has explored miRNA involvement in the development and fate of immune cells and in both the innate and adaptive immune responses whereby strong evidence links miRNA expression to signalling pathways and receptors with critical roles in the inflammatory response such as NF-κB and the toll-like receptors, respectively. Recent studies have revealed that unique miRNA expression profiles exist in inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and lung cancer. Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders. Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered. Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief. Here we discuss the current understanding of miRNA involvement in innate immunity, specifically in LPS/TLR4 signalling and in the progression of the chronic inflammatory lung diseases cystic fibrosis, COPD and asthma. miRNA in lung cancer and IPF are also reviewed.

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Related in: MedlinePlus

Representation of miRNA induction and biogenesis. Induction of miRNA expression occurs via transcription factors and other regulatory influences. Primary miRNA transcripts (pri-miRNA) produced in the nucleus are generally processed by Drosha and DGCR8 into pre-miRNA hairpin structures and transported to the cytoplasm by Exportin 5. The pre-miRNA is processed by Dicer into a miRNA duplex where the mature miRNA guide strand is incorporated into a miRNA-induced silencing complex (miRISC) and the miRNA* strand is degraded. Incorporation into miRISC is facilitated by AGO proteins. Importin 8 aids subsequent transport of the miRNA to the target mRNA where binding to the 3'UTR occurs resulting in translational repression or degradation.
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Figure 1: Representation of miRNA induction and biogenesis. Induction of miRNA expression occurs via transcription factors and other regulatory influences. Primary miRNA transcripts (pri-miRNA) produced in the nucleus are generally processed by Drosha and DGCR8 into pre-miRNA hairpin structures and transported to the cytoplasm by Exportin 5. The pre-miRNA is processed by Dicer into a miRNA duplex where the mature miRNA guide strand is incorporated into a miRNA-induced silencing complex (miRISC) and the miRNA* strand is degraded. Incorporation into miRISC is facilitated by AGO proteins. Importin 8 aids subsequent transport of the miRNA to the target mRNA where binding to the 3'UTR occurs resulting in translational repression or degradation.

Mentions: Primary miRNA (pri-miRNA) originate in the nucleus as single long transcripts up to 1000 nucleotides long which can be processed by the RNase III enzyme Drosha and the RNA binding protein DGCR8 into pre-cursor hairpin structures ~ 70-100nt long termed "pre-miRNA" [13-15]. Transport to the cytoplasm is via Exportin 5 where the pre-miRNA is further processed by Dicer into a miRNA duplex consisting of the mature miRNA and the so called miRNA* strand (which is generally degraded) [16]. Incorporation of the mature miRNA into a miRNA-induced silencing complex (miRISC) is facilitated by Argonate protein involvement and transport to the target mRNA has recently been reported to involve importin 8 [17] (Figure 1). Single miRNA can exist in introns and exons of so called host genes, whilst certain groups of miRNAs are present in clusters in the genome for example the miR-17-92 family. Within each miRNA there exists a 2-8 nucleotide "seed region" thought to be critical for target selection [18]. Mature miRNAs use this seed region to bind selectively to miRNA recognition elements (MRE) within the 3' untranslated region (3'UTR) of target mRNAs. Different target genes may contain several MREs and therefore be regulated by numerous miRNAs. The number of and distance between MREs are considered important for the biological activity of miRNAs. Targeting and subsequent repression of transcripts may also occur at the 5'UTR with equal efficacy [19]. However, the majority of studies have revolved around determination of miRNA:mRNA interactions at the 3'UTR.


MicroRNAs in inflammatory lung disease--master regulators or target practice?

Oglesby IK, McElvaney NG, Greene CM - Respir. Res. (2010)

Representation of miRNA induction and biogenesis. Induction of miRNA expression occurs via transcription factors and other regulatory influences. Primary miRNA transcripts (pri-miRNA) produced in the nucleus are generally processed by Drosha and DGCR8 into pre-miRNA hairpin structures and transported to the cytoplasm by Exportin 5. The pre-miRNA is processed by Dicer into a miRNA duplex where the mature miRNA guide strand is incorporated into a miRNA-induced silencing complex (miRISC) and the miRNA* strand is degraded. Incorporation into miRISC is facilitated by AGO proteins. Importin 8 aids subsequent transport of the miRNA to the target mRNA where binding to the 3'UTR occurs resulting in translational repression or degradation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984500&req=5

Figure 1: Representation of miRNA induction and biogenesis. Induction of miRNA expression occurs via transcription factors and other regulatory influences. Primary miRNA transcripts (pri-miRNA) produced in the nucleus are generally processed by Drosha and DGCR8 into pre-miRNA hairpin structures and transported to the cytoplasm by Exportin 5. The pre-miRNA is processed by Dicer into a miRNA duplex where the mature miRNA guide strand is incorporated into a miRNA-induced silencing complex (miRISC) and the miRNA* strand is degraded. Incorporation into miRISC is facilitated by AGO proteins. Importin 8 aids subsequent transport of the miRNA to the target mRNA where binding to the 3'UTR occurs resulting in translational repression or degradation.
Mentions: Primary miRNA (pri-miRNA) originate in the nucleus as single long transcripts up to 1000 nucleotides long which can be processed by the RNase III enzyme Drosha and the RNA binding protein DGCR8 into pre-cursor hairpin structures ~ 70-100nt long termed "pre-miRNA" [13-15]. Transport to the cytoplasm is via Exportin 5 where the pre-miRNA is further processed by Dicer into a miRNA duplex consisting of the mature miRNA and the so called miRNA* strand (which is generally degraded) [16]. Incorporation of the mature miRNA into a miRNA-induced silencing complex (miRISC) is facilitated by Argonate protein involvement and transport to the target mRNA has recently been reported to involve importin 8 [17] (Figure 1). Single miRNA can exist in introns and exons of so called host genes, whilst certain groups of miRNAs are present in clusters in the genome for example the miR-17-92 family. Within each miRNA there exists a 2-8 nucleotide "seed region" thought to be critical for target selection [18]. Mature miRNAs use this seed region to bind selectively to miRNA recognition elements (MRE) within the 3' untranslated region (3'UTR) of target mRNAs. Different target genes may contain several MREs and therefore be regulated by numerous miRNAs. The number of and distance between MREs are considered important for the biological activity of miRNAs. Targeting and subsequent repression of transcripts may also occur at the 5'UTR with equal efficacy [19]. However, the majority of studies have revolved around determination of miRNA:mRNA interactions at the 3'UTR.

Bottom Line: Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders.Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered.Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief.

View Article: PubMed Central - HTML - PubMed

Affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

ABSTRACT
MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs with immense significance in numerous biological processes. When aberrantly expressed miRNAs have been shown to play a role in the pathogenesis of several disease states. Extensive research has explored miRNA involvement in the development and fate of immune cells and in both the innate and adaptive immune responses whereby strong evidence links miRNA expression to signalling pathways and receptors with critical roles in the inflammatory response such as NF-κB and the toll-like receptors, respectively. Recent studies have revealed that unique miRNA expression profiles exist in inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and lung cancer. Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders. Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered. Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief. Here we discuss the current understanding of miRNA involvement in innate immunity, specifically in LPS/TLR4 signalling and in the progression of the chronic inflammatory lung diseases cystic fibrosis, COPD and asthma. miRNA in lung cancer and IPF are also reviewed.

Show MeSH
Related in: MedlinePlus