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MicroRNA networks in mouse lung organogenesis.

Dong J, Jiang G, Asmann YW, Tomaszek S, Jen J, Kislinger T, Wigle DA - PLoS ONE (2010)

Bottom Line: Of 1345 proteins analyzed, 55% appeared to be regulated in this manner with a direct correlation between miRNA and protein level, but without detectable change in mRNA levels.Systematic analysis of microRNA, mRNA, and protein levels over the time course of lung organogenesis demonstrates dynamic regulation and reveals 2 distinct patterns of miRNA-mRNA interaction.The translation of target proteins affected by miRNAs independent of changes in mRNA level appears to be a prominent mechanism of developmental regulation in lung organogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of General Thoracic Surgery, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota, USA.

ABSTRACT

Background: MicroRNAs (miRNAs) are known to be important regulators of both organ development and tumorigenesis. MiRNA networks and their regulation of messenger RNA (mRNA) translation and protein expression in specific biological processes are poorly understood.

Methods: We explored the dynamic regulation of miRNAs in mouse lung organogenesis. Comprehensive miRNA and mRNA profiling was performed encompassing all recognized stages of lung development beginning at embryonic day 12 and continuing to adulthood. We analyzed the expression patterns of dynamically regulated miRNAs and mRNAs using a number of statistical and computational approaches, and in an integrated manner with protein levels from an existing mass-spectrometry derived protein database for lung development.

Results: In total, 117 statistically significant miRNAs were dynamically regulated during mouse lung organogenesis and clustered into distinct temporal expression patterns. 11,220 mRNA probes were also shown to be dynamically regulated and clustered into distinct temporal expression patterns, with 3 major patterns accounting for 75% of all probes. 3,067 direct miRNA-mRNA correlation pairs were identified involving 37 miRNAs. Two defined correlation patterns were observed upon integration with protein data: 1) increased levels of specific miRNAs directly correlating with downregulation of predicted mRNA targets; and 2) increased levels of specific miRNAs directly correlating with downregulation of translated target proteins without detectable changes in mRNA levels. Of 1345 proteins analyzed, 55% appeared to be regulated in this manner with a direct correlation between miRNA and protein level, but without detectable change in mRNA levels.

Conclusion: Systematic analysis of microRNA, mRNA, and protein levels over the time course of lung organogenesis demonstrates dynamic regulation and reveals 2 distinct patterns of miRNA-mRNA interaction. The translation of target proteins affected by miRNAs independent of changes in mRNA level appears to be a prominent mechanism of developmental regulation in lung organogenesis.

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Visualization of chromosome localization of mouse miRNAs.Chromosome localization of (A) total 521 mouse miRNAs (Sanger version 10.1) and (B) 117 significant miRNAs in different clusters (marked in different colors) involved in lung development. The scale is given to make those miRNAs having the same or very close chromosome location displayed in a vertical line. (C) Numbers of direct mRNA targets for each miRNA detected by miRNA/mRNA correlation. 30 miRNAs with multiple direct targets are annotated. MiRNAs within clusters are boxed. (D) Numbers of direct protein targets detected for each miRNA by miRNA/protein correlation. The top 30 miRNAs are annotated.
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pone-0010854-g004: Visualization of chromosome localization of mouse miRNAs.Chromosome localization of (A) total 521 mouse miRNAs (Sanger version 10.1) and (B) 117 significant miRNAs in different clusters (marked in different colors) involved in lung development. The scale is given to make those miRNAs having the same or very close chromosome location displayed in a vertical line. (C) Numbers of direct mRNA targets for each miRNA detected by miRNA/mRNA correlation. 30 miRNAs with multiple direct targets are annotated. MiRNAs within clusters are boxed. (D) Numbers of direct protein targets detected for each miRNA by miRNA/protein correlation. The top 30 miRNAs are annotated.

Mentions: MiRNAs are found throughout mammalian genomes. Half of the known miRNAs are located inside or close to fragile sites which are genomically unstable and common breakpoints associated with cancer. Nearly 40% of miRNAs exist in genomic clusters. Some clusters reflect the processing of a number of miRNAs from a single large polycistronic transcript such that presumably all of the miRNAs are under control of the same promoter and in the same transcriptional orientation [27]. With the stringent criteria that a cluster should consist of more than two members positioned within 1 Mb, there are 22 miRNA clusters identified in mouse [27], [28], [29]. The largest is the miR-127 cluster with greater than 50 members on mouse chromosome 12 (Chr.12). Other large clusters include the miR-29a cluster on Chr.6, the miR-23a cluster on chr.8, the miR-17-92 cluster on Chr.14 and the miR-106a cluster on Chr.X (Figure 4A). Significant miRNAs dynamically regulated in lung development were positioned throughout the genome except for Chr.5 and Chr.Y (Figure 4B). 23 miRNAs belonging to the miR-127 cluster were increased, whereas all 6 miRNAs in the miRNA-17-92 cluster (mir-17, 18a, 19a, 19b-1, 20a, and 92-1) and 3 miRNAs (mir-20b, 90a-2 and 106a) in the miR-106a cluster that all belong to miRNA cluster 5 were dramatically decreased (Figure 4). Interestingly, almost all 23 miRNAs in the miR-127 cluster that have the same strand orientation belong to miRNA Cluster 4 and have highest expression around E18. Within the miR-127 cluster, no miRNA targets were identified by miRNA/mRNA pairing (Figure 4C), while all had direct mRNA targets when miRNA/protein pairs were analyzed, such as miR-380-5p, miR-370, and miR-434. This suggests that the miR-127 cluster may be involved in part of the regulation of the start of alveolar formation by inhibiting mRNA translation of specific targets without changes in mRNA levels. A number of further targets were identified through miRNA/protein correlations, such as the mir-200 family (miR-200a, miR-200b and miR-200c), miR-191, miR-195, miR-301, and miR-322 (Figure 4D).


MicroRNA networks in mouse lung organogenesis.

Dong J, Jiang G, Asmann YW, Tomaszek S, Jen J, Kislinger T, Wigle DA - PLoS ONE (2010)

Visualization of chromosome localization of mouse miRNAs.Chromosome localization of (A) total 521 mouse miRNAs (Sanger version 10.1) and (B) 117 significant miRNAs in different clusters (marked in different colors) involved in lung development. The scale is given to make those miRNAs having the same or very close chromosome location displayed in a vertical line. (C) Numbers of direct mRNA targets for each miRNA detected by miRNA/mRNA correlation. 30 miRNAs with multiple direct targets are annotated. MiRNAs within clusters are boxed. (D) Numbers of direct protein targets detected for each miRNA by miRNA/protein correlation. The top 30 miRNAs are annotated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2877109&req=5

pone-0010854-g004: Visualization of chromosome localization of mouse miRNAs.Chromosome localization of (A) total 521 mouse miRNAs (Sanger version 10.1) and (B) 117 significant miRNAs in different clusters (marked in different colors) involved in lung development. The scale is given to make those miRNAs having the same or very close chromosome location displayed in a vertical line. (C) Numbers of direct mRNA targets for each miRNA detected by miRNA/mRNA correlation. 30 miRNAs with multiple direct targets are annotated. MiRNAs within clusters are boxed. (D) Numbers of direct protein targets detected for each miRNA by miRNA/protein correlation. The top 30 miRNAs are annotated.
Mentions: MiRNAs are found throughout mammalian genomes. Half of the known miRNAs are located inside or close to fragile sites which are genomically unstable and common breakpoints associated with cancer. Nearly 40% of miRNAs exist in genomic clusters. Some clusters reflect the processing of a number of miRNAs from a single large polycistronic transcript such that presumably all of the miRNAs are under control of the same promoter and in the same transcriptional orientation [27]. With the stringent criteria that a cluster should consist of more than two members positioned within 1 Mb, there are 22 miRNA clusters identified in mouse [27], [28], [29]. The largest is the miR-127 cluster with greater than 50 members on mouse chromosome 12 (Chr.12). Other large clusters include the miR-29a cluster on Chr.6, the miR-23a cluster on chr.8, the miR-17-92 cluster on Chr.14 and the miR-106a cluster on Chr.X (Figure 4A). Significant miRNAs dynamically regulated in lung development were positioned throughout the genome except for Chr.5 and Chr.Y (Figure 4B). 23 miRNAs belonging to the miR-127 cluster were increased, whereas all 6 miRNAs in the miRNA-17-92 cluster (mir-17, 18a, 19a, 19b-1, 20a, and 92-1) and 3 miRNAs (mir-20b, 90a-2 and 106a) in the miR-106a cluster that all belong to miRNA cluster 5 were dramatically decreased (Figure 4). Interestingly, almost all 23 miRNAs in the miR-127 cluster that have the same strand orientation belong to miRNA Cluster 4 and have highest expression around E18. Within the miR-127 cluster, no miRNA targets were identified by miRNA/mRNA pairing (Figure 4C), while all had direct mRNA targets when miRNA/protein pairs were analyzed, such as miR-380-5p, miR-370, and miR-434. This suggests that the miR-127 cluster may be involved in part of the regulation of the start of alveolar formation by inhibiting mRNA translation of specific targets without changes in mRNA levels. A number of further targets were identified through miRNA/protein correlations, such as the mir-200 family (miR-200a, miR-200b and miR-200c), miR-191, miR-195, miR-301, and miR-322 (Figure 4D).

Bottom Line: Of 1345 proteins analyzed, 55% appeared to be regulated in this manner with a direct correlation between miRNA and protein level, but without detectable change in mRNA levels.Systematic analysis of microRNA, mRNA, and protein levels over the time course of lung organogenesis demonstrates dynamic regulation and reveals 2 distinct patterns of miRNA-mRNA interaction.The translation of target proteins affected by miRNAs independent of changes in mRNA level appears to be a prominent mechanism of developmental regulation in lung organogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of General Thoracic Surgery, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota, USA.

ABSTRACT

Background: MicroRNAs (miRNAs) are known to be important regulators of both organ development and tumorigenesis. MiRNA networks and their regulation of messenger RNA (mRNA) translation and protein expression in specific biological processes are poorly understood.

Methods: We explored the dynamic regulation of miRNAs in mouse lung organogenesis. Comprehensive miRNA and mRNA profiling was performed encompassing all recognized stages of lung development beginning at embryonic day 12 and continuing to adulthood. We analyzed the expression patterns of dynamically regulated miRNAs and mRNAs using a number of statistical and computational approaches, and in an integrated manner with protein levels from an existing mass-spectrometry derived protein database for lung development.

Results: In total, 117 statistically significant miRNAs were dynamically regulated during mouse lung organogenesis and clustered into distinct temporal expression patterns. 11,220 mRNA probes were also shown to be dynamically regulated and clustered into distinct temporal expression patterns, with 3 major patterns accounting for 75% of all probes. 3,067 direct miRNA-mRNA correlation pairs were identified involving 37 miRNAs. Two defined correlation patterns were observed upon integration with protein data: 1) increased levels of specific miRNAs directly correlating with downregulation of predicted mRNA targets; and 2) increased levels of specific miRNAs directly correlating with downregulation of translated target proteins without detectable changes in mRNA levels. Of 1345 proteins analyzed, 55% appeared to be regulated in this manner with a direct correlation between miRNA and protein level, but without detectable change in mRNA levels.

Conclusion: Systematic analysis of microRNA, mRNA, and protein levels over the time course of lung organogenesis demonstrates dynamic regulation and reveals 2 distinct patterns of miRNA-mRNA interaction. The translation of target proteins affected by miRNAs independent of changes in mRNA level appears to be a prominent mechanism of developmental regulation in lung organogenesis.

Show MeSH
Related in: MedlinePlus