MicroRNAs (miRNAs) critically modulate stem cell pluripotency and their differentiation , but the precise mechanistic mechanism remains largely unknown. This study systematically reveals the functional and mechanistic roles of miRNAs in mouse pluripotent stem cells by analyzing the genome-wide physical interactions between all activated miRNAs and their targets. Generally, miRNAs vary their physical targets and functions with the switch of pluripotency to differentiation state. During pluripotency miRNAs primarily and mechanistically target and repress developmental processes, but surprisingly  miRNAs do not directly target the pluripotent core factors but only mediate extrinsic signal pathways associated with pluripotency. During differentiation miRNAs mechanistically inhibit metabolism and directly repress the pluripotency . Interestingly,  DNA methylation in enhancer regions mediates these miRNA activations. Together, under mediation by DNA methylation, miRNAs directly repress development and mechanistically modulate the pluripotent signal pathways to help stem cells maintain pluripotency; yet miRNAs directly repress both pluripotency and metabolism to facilitate cell differentiation .
MicroRNAs (miRNAs) critically modulate stem cell pluripotency , but the precise mechanistic mechanism remains largely unknown. This study systematically reveals the general mechanistic roles of miRNAs in mouse stem cells by analyzing global physical interactions between miRNAs and their targets. Generally, miRNAs primarily repress developmental processes, but surprisingly the top up-regulated miRNAs do not directly target the pluripotent core factors as thought; they only target extrinsic signal pathways associated with pluripotency. This suggested that the most important miRNAs in stem cells may only indirectly regulate the pluripotency via the genetic system . Interestingly, miRNAs predominately target and repress DNA methyltransferase, core enzymes for DNA methylation, and decreasing methylation in turn activates the top miRNAs. This system-wide circuit between up-regulated miRNAs and the repressed DNA methylation system would eventually activate pluripotent core factors for pluripotency. Therefore, miRNAs systematically repress development and inhibit the epigenetic system to modulate stem cell pluripotency .
D
and their differentiation
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functional and
general
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pluripotent
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the genome-wide
global
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all activated
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vary their physical targets and functions with the switch of pluripotency to differentiation state. During pluripotency miRNAs primarily and mechanistically target and
primarily
A
the top up-regulated
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but only mediate
as thought; they only target
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During differentiation miRNAs mechanistically inhibit metabolism and directly repress the pluripotency
This suggested that the most important miRNAs in stem cells may only indirectly regulate the pluripotency via the genetic system
A
miRNAs predominately target and repress DNA methyltransferase, core enzymes for
D
methylation in enhancer regions mediates these miRNA activations. Together, under mediation by DNA
R
miRNAs directly repress development and mechanistically modulate the pluripotent signal pathways to help stem cells maintain pluripotency; yet miRNAs directly repress both pluripotency and metabolism to facilitate cell differentiation
and decreasing methylation in turn activates the top miRNAs. This system-wide circuit between up-regulated miRNAs and the repressed DNA methylation system would eventually activate pluripotent core factors for pluripotency. Therefore, miRNAs systematically repress development and inhibit the epigenetic system to modulate stem cell pluripotency