Abstract
When embryonic stem cells (ESCs) differentiate, they must both silence the ESC self-renewal program and activate new tissue-specific programs. In the absence of DGCR8 (Dgcr8(-/-)), a protein required for microRNA (miRNA) biogenesis, mouse ESCs are unable to silence self-renewal. Here we show that the introduction of let-7 miRNAs-a family of miRNAs highly expressed in somatic cells-can suppress self-renewal in Dgcr8(-/-) but not wild-type ESCs. Introduction of ESC cell cycle regulating (ESCC) miRNAs into the Dgcr8(-/-) ESCs blocks the capacity of let-7 to suppress self-renewal. Profiling and bioinformatic analyses show that let-7 inhibits whereas ESCC miRNAs indirectly activate numerous self-renewal genes. Furthermore, inhibition of the let-7 family promotes de-differentiation of somatic cells to induced pluripotent stem cells. Together, these findings show how the ESCC and let-7 miRNAs act through common pathways to alternatively stabilize the self-renewing versus differentiated cell fates.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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3' Untranslated Regions / genetics
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Animals
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Cell Dedifferentiation / genetics
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Cell Lineage / genetics
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Cell Proliferation*
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Cellular Reprogramming / genetics
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Computational Biology
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DNA-Binding Proteins / genetics
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Embryonic Stem Cells / cytology*
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Embryonic Stem Cells / metabolism*
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Gene Silencing
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Genes, myc / genetics
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Induced Pluripotent Stem Cells / cytology
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Induced Pluripotent Stem Cells / metabolism
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Mice
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MicroRNAs / antagonists & inhibitors
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MicroRNAs / genetics*
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MicroRNAs / metabolism*
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Open Reading Frames / genetics
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Proteins / genetics
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RNA-Binding Proteins / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
Substances
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3' Untranslated Regions
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DNA-Binding Proteins
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Dgcr8 protein, mouse
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Lin-28 protein, mouse
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MicroRNAs
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Proteins
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RNA-Binding Proteins
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Sall4 protein, mouse
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Transcription Factors
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mirnlet7 microRNA, mouse