Abstract
Although many changes have been discovered during heart maturation, the genetic mechanisms involved in the changes between immature and mature myocardium have only been partially elucidated. Here, gene expression profile changed between the human fetal and adult heart was characterized. A human microarray was applied to define the gene expression signatures of the fetal (13–17 weeks of gestation, n = 4) and adult hearts (30–40 years old, n = 4). Gene ontology analyses, pathway analyses, gene set enrichment analyses, and signal transduction network were performed to predict the function of the differentially expressed genes. Ten mRNAs were confirmed by quantificational real-time polymerase chain reaction. 5547 mRNAs were found to be significantly differentially expressed. “Cell cycle” was the most enriched pathway in the down-regulated genes. EFGR, IGF1R, and ITGB1 play a central role in the regulation of heart development. EGFR, IGF1R, and FGFR2 were the core genes regulating cardiac cell proliferation. The quantificational real-time polymerase chain reaction results were concordant with the microarray data. Our data identified the transcriptional regulation of heart development in the second trimester and the potential regulators that play a prominent role in the regulation of heart development and cardiac cells proliferation.
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Funding
This work was supported by National Natural Science Foundation of China (Grant Number 81670255), Zhejiang Provincial Natural Science Foundation of China (Grant Number LY14H020008), Science and Technology Department of Zhejiang Province (Grant Number 2015C33163), Zhejiang Provincial Natural Science Foundation of China (Grant Number LY13H020005), Scientific Research Foundation of Wenzhou (Grant Number Y20150015), Zhejiang Provincial Medical and Health Science and Technology plan (Grant Number 2016KYB197).
Authors’ Contributions
MPC designed the study; JW and ZMG analyzed the data and wrote the manuscript; LLP, XLC, and JTZ contributed to the collection of samples and analyzed the data; ML revised the paper. All authors read and approved the final version.
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Zhimin Geng and Jue Wang have contributed equally to this study.
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Extent of cardiomyocyte proliferation in fetal and adult hearts. Immunofluorescent staining shows the proliferating Ki-67+ cardiomyocytes (green arrow heads) in the fetal heart and no proliferating Ki-67+ cardiomyocytes in the adult heart. Scale bar: 50 μm. Supplementary material 1 (TIF 4921 KB)
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Differentially expressed genes between the fetal and adult heart. The scatterplot (A) is a visualization used to assess the variation between the chips. The X and Y axes in the scatterplot represent the normalized signal values of each group (log2 scaled). The green lines represent FC (FC = 2.0) lines. Hierarchical clustering (B) shows the expression values of differentially expressed genes. ‘Red’ indicates higher expression, whereas ‘green’ indicates lower expression. The bar code represents the color scale of log2 transformed values. Supplementary material 2 (TIF 2771 KB)
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GO analysis. All the gene ontology terms that exhibited significant differences between the fetal hearts and adult hearts are listed. A, Gene ontology terms involved in the down-regulated genes in the adult group. B, Gene ontology terms involved in the up-regulated genes. Higher -lg P value indicates higher significance level. Supplementary material 3 (TIF 1449 KB)
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Cell cycle pathway. Red frames represent the down-regulated genes and purple frames represent the up-regulated genes in the adult group. Supplementary material 4 (TIF 3946 KB)
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GSEA of the cell cycle pathway gene set. GSEA analysis indicated that the cell cycle pathway gene set was significantly enriched (A). The x-axis represents the genes ranked from the most down-regulated to the most up-regulated in the adult group. The y-axis represents enrichment score (ES), which increases when a gene is in the gene set and decreases when it is not. FDR q-value = 0.043, P < 0.001. B represents the genes included in the cell cycle pathway gene sets, with “red” representing the up-regulated genes and blue representing the down-regulated genes. Supplementary material 5 (TIF 3234 KB)
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Signal transduction network of the focused genes. Red circles represent down-regulated genes and blue ones represent up-regulated genes in the adult group. The larger the circle is, the higher the degree would be. The interactions between the genes include binding/association (b), phosphorylation (pho), ubiquination (ubi), expression (ex), dephosphorylation (de), activation (a) and indirect (indi, dotted line). Supplementary material 6 (TIF 1149 KB)
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Geng, Z., Wang, J., Pan, L. et al. Microarray Analysis of Differential Gene Expression Profile Between Human Fetal and Adult Heart. Pediatr Cardiol 38, 700–706 (2017). https://doi.org/10.1007/s00246-017-1569-x
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DOI: https://doi.org/10.1007/s00246-017-1569-x