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Systematically dissecting the global mechanism of miRNA functions in mouse pluripotent stem cells.

Wang A, He Q, Zhong Y - BMC Genomics (2015)

Bottom Line: Surprisingly, during the pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as previously thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes.MiRNAs vary their functions with stem cell states.While miRNAs directly repress pluripotent core factors to facilitate differentiation during the differentiation state, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development in the pluripotent state.

View Article: PubMed Central - PubMed

Affiliation: School of medicine, University of California San Francisco, S-1268, Medical Sciences Building, 513 Parnassus Ave, San Francisco, CA, 94143, USA. anyou.wang@alumni.ucr.edu.

ABSTRACT

Background: MicroRNAs (miRNAs) critically modulate stem cell properties like pluripotency, but the fundamental mechanism remains largely unknown.

Method: This study systematically analyzes multiple-omics data and builds a systems physical network including genome-wide interactions between miRNAs and their targets to reveal the systems mechanism of miRNA functions in mouse pluripotent stem cells.

Results: Globally, miRNAs directly repress the pluripotent core factors during differentiation state. Surprisingly, during the pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as previously thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes. Furthermore, at the pluripotent state miRNAs predominately repress DNA methyltransferases, the core enzymes for DNA methylation. The decreasing methylation repressed by miRNAs in turn activates the top miRNAs and pluripotent core factors, creating an active circuit system to modulate pluripotency.

Conclusion: MiRNAs vary their functions with stem cell states. While miRNAs directly repress pluripotent core factors to facilitate differentiation during the differentiation state, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development in the pluripotent state.

No MeSH data available.


Related in: MedlinePlus

DNA methylation mediates miRNA activations in stem cells. a, The methylation levels upstream and downstream from the miRNA start site. Down-regulated miRNAs have significantly higher methylation in upstream region when compared with up-regulated miRNAs. b, Detailed methylation profiling for regions that are 2000 bp upstream from the activated miRNAs. The top 30 down-regulated miRNAs (Additional file 1: Table S2) have higher methylation around -1000 bp (green highlighted in middle panel) than that of the top 30 up-regulated miRNAs (Additional file 1: Table S2, upper panel). The methylation profiling of a single down-regulated miRNA-133 as a representative example (bottom panel). c. Negative correlation between DNA methylation and miRNA expression. Red line represents regression line
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Fig8: DNA methylation mediates miRNA activations in stem cells. a, The methylation levels upstream and downstream from the miRNA start site. Down-regulated miRNAs have significantly higher methylation in upstream region when compared with up-regulated miRNAs. b, Detailed methylation profiling for regions that are 2000 bp upstream from the activated miRNAs. The top 30 down-regulated miRNAs (Additional file 1: Table S2) have higher methylation around -1000 bp (green highlighted in middle panel) than that of the top 30 up-regulated miRNAs (Additional file 1: Table S2, upper panel). The methylation profiling of a single down-regulated miRNA-133 as a representative example (bottom panel). c. Negative correlation between DNA methylation and miRNA expression. Red line represents regression line

Mentions: To search the mechanism controlling the miRNA activations, this study turned to the genome-wide sequencing of DNA methylation in stem cells and methylation-loss-stem cells [30] (Additional file 1: Table S1, materials and methods). A total of 2000 bp in each upstream and downstream of start sites of all activated miRNAs were examined. While the DNA methylation in the downstream of up-regulated miRNAs is not different from that of down-regulated miRNAs (p > 0.1899), the down-regulated miRNAs hold significantly higher methylation upstream than up-regulated miRNAs (p < 3.685e-05, Fig. 8a). Surprisingly, the biggest difference locates in ~1000 bp up-stream instead of immediate up-stream (p < 1.265e-06, Fig. 8b). Furthermore, these differences are overall negatively correlated to miRNA expressions with correlation coefficient of −0.35 and p-value < 0.05 (Fig. 8c). This suggested that the difference in DNA methylation accounts for the miRNA activations. This parallels a recent observation showing that the loss of DNA methylation significantly increases miRNA expressions [29]. Therefore, miRNA activations and their network are mediated by DNA methylation in ~1000 bp upstream regions.Fig. 8


Systematically dissecting the global mechanism of miRNA functions in mouse pluripotent stem cells.

Wang A, He Q, Zhong Y - BMC Genomics (2015)

DNA methylation mediates miRNA activations in stem cells. a, The methylation levels upstream and downstream from the miRNA start site. Down-regulated miRNAs have significantly higher methylation in upstream region when compared with up-regulated miRNAs. b, Detailed methylation profiling for regions that are 2000 bp upstream from the activated miRNAs. The top 30 down-regulated miRNAs (Additional file 1: Table S2) have higher methylation around -1000 bp (green highlighted in middle panel) than that of the top 30 up-regulated miRNAs (Additional file 1: Table S2, upper panel). The methylation profiling of a single down-regulated miRNA-133 as a representative example (bottom panel). c. Negative correlation between DNA methylation and miRNA expression. Red line represents regression line
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4488055&req=5

Fig8: DNA methylation mediates miRNA activations in stem cells. a, The methylation levels upstream and downstream from the miRNA start site. Down-regulated miRNAs have significantly higher methylation in upstream region when compared with up-regulated miRNAs. b, Detailed methylation profiling for regions that are 2000 bp upstream from the activated miRNAs. The top 30 down-regulated miRNAs (Additional file 1: Table S2) have higher methylation around -1000 bp (green highlighted in middle panel) than that of the top 30 up-regulated miRNAs (Additional file 1: Table S2, upper panel). The methylation profiling of a single down-regulated miRNA-133 as a representative example (bottom panel). c. Negative correlation between DNA methylation and miRNA expression. Red line represents regression line
Mentions: To search the mechanism controlling the miRNA activations, this study turned to the genome-wide sequencing of DNA methylation in stem cells and methylation-loss-stem cells [30] (Additional file 1: Table S1, materials and methods). A total of 2000 bp in each upstream and downstream of start sites of all activated miRNAs were examined. While the DNA methylation in the downstream of up-regulated miRNAs is not different from that of down-regulated miRNAs (p > 0.1899), the down-regulated miRNAs hold significantly higher methylation upstream than up-regulated miRNAs (p < 3.685e-05, Fig. 8a). Surprisingly, the biggest difference locates in ~1000 bp up-stream instead of immediate up-stream (p < 1.265e-06, Fig. 8b). Furthermore, these differences are overall negatively correlated to miRNA expressions with correlation coefficient of −0.35 and p-value < 0.05 (Fig. 8c). This suggested that the difference in DNA methylation accounts for the miRNA activations. This parallels a recent observation showing that the loss of DNA methylation significantly increases miRNA expressions [29]. Therefore, miRNA activations and their network are mediated by DNA methylation in ~1000 bp upstream regions.Fig. 8

Bottom Line: Surprisingly, during the pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as previously thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes.MiRNAs vary their functions with stem cell states.While miRNAs directly repress pluripotent core factors to facilitate differentiation during the differentiation state, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development in the pluripotent state.

View Article: PubMed Central - PubMed

Affiliation: School of medicine, University of California San Francisco, S-1268, Medical Sciences Building, 513 Parnassus Ave, San Francisco, CA, 94143, USA. anyou.wang@alumni.ucr.edu.

ABSTRACT

Background: MicroRNAs (miRNAs) critically modulate stem cell properties like pluripotency, but the fundamental mechanism remains largely unknown.

Method: This study systematically analyzes multiple-omics data and builds a systems physical network including genome-wide interactions between miRNAs and their targets to reveal the systems mechanism of miRNA functions in mouse pluripotent stem cells.

Results: Globally, miRNAs directly repress the pluripotent core factors during differentiation state. Surprisingly, during the pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as previously thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes. Furthermore, at the pluripotent state miRNAs predominately repress DNA methyltransferases, the core enzymes for DNA methylation. The decreasing methylation repressed by miRNAs in turn activates the top miRNAs and pluripotent core factors, creating an active circuit system to modulate pluripotency.

Conclusion: MiRNAs vary their functions with stem cell states. While miRNAs directly repress pluripotent core factors to facilitate differentiation during the differentiation state, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development in the pluripotent state.

No MeSH data available.


Related in: MedlinePlus