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Genome-wide transcriptional profiling reveals microRNA-correlated genes and biological processes in human lymphoblastoid cell lines.

Wang L, Oberg AL, Asmann YW, Sicotte H, McDonnell SK, Riska SM, Liu W, Steer CJ, Subramanian S, Cunningham JM, Cerhan JR, Thibodeau SN - PLoS ONE (2009)

Bottom Line: To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts.Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. wang.liang@mayo.edu

ABSTRACT

Background: Expression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs.

Methodology/principal findings: To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.

Conclusions/significance: This study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.

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Frequency and significance level of miRNA-correlated genes.A. 90 of the 366 individual miRNAs are correlated with at least one mRNA. We align the 90 miRNAs on 20 of 24 chromosomes based on their genomic locations (X axis). For each miRNA, the number of the correlated mRNA probes is demonstrated on Y axis (red dot). For example, miR-363 on Xq26.2 is correlated with 672 mRNA probes. Both miR-181b (correlated with 468 mRNA probes) and miR-181a (correlated with 440 mRNA probes) have two copies, each on different chromosomes (1 and 9). B. Among 11,417 known genes (14,174 mRNA probes), we successfully map 11,278 individual genes on the 24 chromosomes (X axis). We plot–log10 values of the correlation coefficient qFDRs between miR-363 and the 11,278 genes along Y axis (blue dot). The horizontal dot line (black) indicates qFDR = 0.01. Above the line are the mRNA probes that were significantly correlated with the miR-363. For example, the miR-363 is significantly associated with the gene SASH (chromosome 6q24.3) at qFDR = 3.70×10−11 (equal to 10.43 of −log scale in the figure).
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pone-0005878-g001: Frequency and significance level of miRNA-correlated genes.A. 90 of the 366 individual miRNAs are correlated with at least one mRNA. We align the 90 miRNAs on 20 of 24 chromosomes based on their genomic locations (X axis). For each miRNA, the number of the correlated mRNA probes is demonstrated on Y axis (red dot). For example, miR-363 on Xq26.2 is correlated with 672 mRNA probes. Both miR-181b (correlated with 468 mRNA probes) and miR-181a (correlated with 440 mRNA probes) have two copies, each on different chromosomes (1 and 9). B. Among 11,417 known genes (14,174 mRNA probes), we successfully map 11,278 individual genes on the 24 chromosomes (X axis). We plot–log10 values of the correlation coefficient qFDRs between miR-363 and the 11,278 genes along Y axis (blue dot). The horizontal dot line (black) indicates qFDR = 0.01. Above the line are the mRNA probes that were significantly correlated with the miR-363. For example, the miR-363 is significantly associated with the gene SASH (chromosome 6q24.3) at qFDR = 3.70×10−11 (equal to 10.43 of −log scale in the figure).

Mentions: We performed pair-wise correlation coefficient analysis to evaluate potential correlations between 366 miRNA and 14,174 mRNA expression levels. When false discovery rate q value (qFDR)<0.01 (approximately p value<0.00076), we detected significant correlation in 7,207 miRNA-mRNA pairs (Table S1), which were involved in 2,448 (17.27%) of the 14,174 mRNA probes and 90 (24.59%) of the 366 miRNAs. Of the 7,207 pairs, 4,085 and 3,122 pairs showed positive and negative correlations, respectively (Table 1, also see Table S2 for all 366*14,174 correlation coefficient r values). The most frequently involved miRNA was miR-363, which was correlated with 672 mRNAs. Cumulative frequency of these correlated genes for each of 366 miRNAs is shown in Figure 1A. Significance level of each mRNA probe for its correlation with miR-363 is demonstrated in Figure 1B.


Genome-wide transcriptional profiling reveals microRNA-correlated genes and biological processes in human lymphoblastoid cell lines.

Wang L, Oberg AL, Asmann YW, Sicotte H, McDonnell SK, Riska SM, Liu W, Steer CJ, Subramanian S, Cunningham JM, Cerhan JR, Thibodeau SN - PLoS ONE (2009)

Frequency and significance level of miRNA-correlated genes.A. 90 of the 366 individual miRNAs are correlated with at least one mRNA. We align the 90 miRNAs on 20 of 24 chromosomes based on their genomic locations (X axis). For each miRNA, the number of the correlated mRNA probes is demonstrated on Y axis (red dot). For example, miR-363 on Xq26.2 is correlated with 672 mRNA probes. Both miR-181b (correlated with 468 mRNA probes) and miR-181a (correlated with 440 mRNA probes) have two copies, each on different chromosomes (1 and 9). B. Among 11,417 known genes (14,174 mRNA probes), we successfully map 11,278 individual genes on the 24 chromosomes (X axis). We plot–log10 values of the correlation coefficient qFDRs between miR-363 and the 11,278 genes along Y axis (blue dot). The horizontal dot line (black) indicates qFDR = 0.01. Above the line are the mRNA probes that were significantly correlated with the miR-363. For example, the miR-363 is significantly associated with the gene SASH (chromosome 6q24.3) at qFDR = 3.70×10−11 (equal to 10.43 of −log scale in the figure).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2691578&req=5

pone-0005878-g001: Frequency and significance level of miRNA-correlated genes.A. 90 of the 366 individual miRNAs are correlated with at least one mRNA. We align the 90 miRNAs on 20 of 24 chromosomes based on their genomic locations (X axis). For each miRNA, the number of the correlated mRNA probes is demonstrated on Y axis (red dot). For example, miR-363 on Xq26.2 is correlated with 672 mRNA probes. Both miR-181b (correlated with 468 mRNA probes) and miR-181a (correlated with 440 mRNA probes) have two copies, each on different chromosomes (1 and 9). B. Among 11,417 known genes (14,174 mRNA probes), we successfully map 11,278 individual genes on the 24 chromosomes (X axis). We plot–log10 values of the correlation coefficient qFDRs between miR-363 and the 11,278 genes along Y axis (blue dot). The horizontal dot line (black) indicates qFDR = 0.01. Above the line are the mRNA probes that were significantly correlated with the miR-363. For example, the miR-363 is significantly associated with the gene SASH (chromosome 6q24.3) at qFDR = 3.70×10−11 (equal to 10.43 of −log scale in the figure).
Mentions: We performed pair-wise correlation coefficient analysis to evaluate potential correlations between 366 miRNA and 14,174 mRNA expression levels. When false discovery rate q value (qFDR)<0.01 (approximately p value<0.00076), we detected significant correlation in 7,207 miRNA-mRNA pairs (Table S1), which were involved in 2,448 (17.27%) of the 14,174 mRNA probes and 90 (24.59%) of the 366 miRNAs. Of the 7,207 pairs, 4,085 and 3,122 pairs showed positive and negative correlations, respectively (Table 1, also see Table S2 for all 366*14,174 correlation coefficient r values). The most frequently involved miRNA was miR-363, which was correlated with 672 mRNAs. Cumulative frequency of these correlated genes for each of 366 miRNAs is shown in Figure 1A. Significance level of each mRNA probe for its correlation with miR-363 is demonstrated in Figure 1B.

Bottom Line: To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts.Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. wang.liang@mayo.edu

ABSTRACT

Background: Expression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs.

Methodology/principal findings: To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.

Conclusions/significance: This study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.

Show MeSH