1. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells.
- Author
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Melton C, Judson RL, and Blelloch R
- Subjects
- 3' Untranslated Regions genetics, Animals, Cell Dedifferentiation genetics, Cell Lineage genetics, Cellular Reprogramming genetics, Computational Biology, DNA-Binding Proteins genetics, Gene Silencing, Genes, myc genetics, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Mice, MicroRNAs antagonists & inhibitors, Open Reading Frames genetics, Proteins genetics, RNA-Binding Proteins genetics, Transcription Factors genetics, Transcription Factors metabolism, Transcription, Genetic, Cell Proliferation, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, MicroRNAs genetics, MicroRNAs metabolism
- 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.
- Published
- 2010
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