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Differential Expression of Plasma Exo-miRNA in Neurodegenerative Diseases by Next-Generation Sequencing

Nie, Chao, Sun, Yuzhe, Zhen, Hefu, Guo, Mei, Ye, Jingyu, Liu, Zhili, Yang, Yan, Zhang, Xiuqing·2020·Frontiers in Neuroscience
DOI 10.3389/fnins.2020.00438PMC PMC7227778
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FIGURE 1 Clusters of miRNA expression and enriched pathways. (A) Heatmap of differentially expressed miRNAs of six clusters. Down, miRNAs with expression of log2(AD/NC) or log2(PD/NC) < -1; NA, miRNAs with expression of -1 < log2(AD/NC) or log2(PD/NC) < 1; Up, miRNAs with expression of log2(AD/NC) or log2(PD/NC) > 1. (B) KEGG pathway of miRNAs from four clusters. Target genes of miRNAs were predicted by miRanda, TargetScan, and RNAhybrid individually. Joint target genes were selected and KEGG pathway enrichment analysis was carried out. Top three pathways of each cluster were shown. The size of the dots represents the -log10(p-value) of each pathway.
FIGURE 1 Clusters of miRNA expression and enriched pathways. (A) Heatmap of differentially expressed miRNAs of six clusters. Down, miRNAs with expression of log2(AD/NC) or log2(PD/NC) < -1; NA, miRNAs with expression of -1 < log2(AD/NC) or log2(PD/NC) < 1; Up, miRNAs with expression of log2(AD/NC) or log2(PD/NC) > 1. (B) KEGG pathway of miRNAs from four clusters. Target genes of miRNAs were predicted by miRanda, TargetScan, and RNAhybrid individually. Joint target genes were selected and KEGG pathway enrichment analysis was carried out. Top three pathways of each cluster were shown. The size of the dots represents the -log10(p-value) of each pathway.CC BY · PubMed Central
FIGURE 2 Heatmap of differential expression levels of miRNAs in AD and PD patients. The color scale shown on the right illustrates the expression level (log2) of a miRNA across all samples. Each row represents significantly declined miRNAs (p < 0.05) in AD or PD patients including 23 declined miRNAs in AD patients and 13 declined miRNAs in PD patients.
FIGURE 2 Heatmap of differential expression levels of miRNAs in AD and PD patients. The color scale shown on the right illustrates the expression level (log2) of a miRNA across all samples. Each row represents significantly declined miRNAs (p < 0.05) in AD or PD patients including 23 declined miRNAs in AD patients and 13 declined miRNAs in PD patients.CC BY · PubMed Central
FIGURE 3 Using significantly altered expression of miRNAs to distinguish AD from NC. Left, Heatmap of significant altered levels of miRNA expression in AD and PD samples. DESeq2 was used to identify significantly up-/down-expressed levels of miRNAs. Fold change was presented by log2 and p-value was presented by log10. PCA and k-means based clustering was performed to distinguish AD samples from NC samples by using significantly expressed levels of miRNAs.
FIGURE 3 Using significantly altered expression of miRNAs to distinguish AD from NC. Left, Heatmap of significant altered levels of miRNA expression in AD and PD samples. DESeq2 was used to identify significantly up-/down-expressed levels of miRNAs. Fold change was presented by log2 and p-value was presented by log10. PCA and k-means based clustering was performed to distinguish AD samples from NC samples by using significantly expressed levels of miRNAs.CC BY · PubMed Central
FIGURE 4 Validation of candidate miRNAs by SC and PC. (A) Fold change (FC) and p-value of candidate miRNA expression in AD samples, FC and p-value were calculated by DESeq2. (B) Spearman Correlation coefficients of miRNA expression between EQ, SC, and PC. (C) Co-inertia analysis of the relationships between EQ, SC, and PC. Monte-Carlo test was carried out, and the significance of correlation could be observed between EQ and SC (p < 0.05). Each sample is represented with two dots connected by a thin line.
FIGURE 4 Validation of candidate miRNAs by SC and PC. (A) Fold change (FC) and p-value of candidate miRNA expression in AD samples, FC and p-value were calculated by DESeq2. (B) Spearman Correlation coefficients of miRNA expression between EQ, SC, and PC. (C) Co-inertia analysis of the relationships between EQ, SC, and PC. Monte-Carlo test was carried out, and the significance of correlation could be observed between EQ and SC (p < 0.05). Each sample is represented with two dots connected by a thin line.CC BY · PubMed Central
FIGURE 5 Analysis of the differences in exosomal miRNA profiles among three isolation methods. (A) Small RNA yield efficiency by three methods. (B) Identified miRNA species by three methods, average of miRNA species from 46 samples. (C) MiRNA total counts by three methods, average of total miRNA counts from 46 samples. (D) Average read length distribution by three methods. (E) Aligned miRNA reads and unmapped reads of 46 samples by three methods. (F) Venn diagram presents all identified miRNAs that are common or unique in the three method datasets. Most (695) miRNAs were common to the three sets. (G–I), Scatter plots reveal correlations between EQ and PC (D), EQ and SC (E), SC and PC (F). Each scatter plot represents relative expression of miRNA profiles obtained by two methods. * represents p < 0.05 in Student’s T-test. ** represents p < 0.01 in Student’s T-test.
FIGURE 5 Analysis of the differences in exosomal miRNA profiles among three isolation methods. (A) Small RNA yield efficiency by three methods. (B) Identified miRNA species by three methods, average of miRNA species from 46 samples. (C) MiRNA total counts by three methods, average of total miRNA counts from 46 samples. (D) Average read length distribution by three methods. (E) Aligned miRNA reads and unmapped reads of 46 samples by three methods. (F) Venn diagram presents all identified miRNAs that are common or unique in the three method datasets. Most (695) miRNAs were common to the three sets. (G–I), Scatter plots reveal correlations between EQ and PC (D), EQ and SC (E), SC and PC (F). Each scatter plot represents relative expression of miRNA profiles obtained by two methods. * represents p < 0.05 in Student’s T-test. ** represents p < 0.01 in Student’s T-test.CC BY · PubMed Central
FIGURE 6 Correlation of EQ, PC, and SC profiles. (A) Grouping information for each sample by PCA. Colors and shapes represent three exosome isolation methods. Y-axis shows the sample number. X-axis shows the grouping information. (B) Venn diagram represents EQ, PC, and SC samples that are grouped into the same clusters. (C) Co-inertia analysis (CIA) of relationships between the EQ and PC miRNA expressional PCA. (D) CIA of relationships between the PC and SC miRNA expressional PCA. (E) CIA of relationships between the EQ and SC miRNA expressional PCA. (C–E) p-value < 0.01 from 99 Monte-Carlo simulations.
FIGURE 6 Correlation of EQ, PC, and SC profiles. (A) Grouping information for each sample by PCA. Colors and shapes represent three exosome isolation methods. Y-axis shows the sample number. X-axis shows the grouping information. (B) Venn diagram represents EQ, PC, and SC samples that are grouped into the same clusters. (C) Co-inertia analysis (CIA) of relationships between the EQ and PC miRNA expressional PCA. (D) CIA of relationships between the PC and SC miRNA expressional PCA. (E) CIA of relationships between the EQ and SC miRNA expressional PCA. (C–E) p-value < 0.01 from 99 Monte-Carlo simulations.CC BY · PubMed Central
FIGURE 7 miRNA expression under three isolation methods. (A) Spearman correlation coefficient was calculated from miRNA expression data in the pair of EQ-PC and SC-PC in each sample. EQ data exhibited higher correlation with PC data than SC with PC. (B) Heatmap of miRNA expression in 46 samples. The top 100 abundant miRNAs were displayed. Higher expression levels were obviously observed in EQ data.
FIGURE 7 miRNA expression under three isolation methods. (A) Spearman correlation coefficient was calculated from miRNA expression data in the pair of EQ-PC and SC-PC in each sample. EQ data exhibited higher correlation with PC data than SC with PC. (B) Heatmap of miRNA expression in 46 samples. The top 100 abundant miRNAs were displayed. Higher expression levels were obviously observed in EQ data.CC BY · PubMed Central

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Metadata

Authors
Nie, C., Sun, Y., Zhen, H., Guo, M., Ye, J., Liu, Z., Yang, Y., & Zhang, X.
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2020-05-07
Volume
14
ISSN
1662-453X
DOI
10.3389/fnins.2020.00438
PMC
PMC7227778
Cited by
89
References
1
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20170412153100794, JSGG20170824152728492)

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