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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.
Pubmed ID: 20054295 RIS Download
Mesh terms: 3' Untranslated Regions | Animals | Cell Dedifferentiation | Cell Lineage | Cell Proliferation | Cellular Reprogramming | Computational Biology | DNA-Binding Proteins | Embryonic Stem Cells | Gene Silencing | Genes, myc | Induced Pluripotent Stem Cells | Mice | MicroRNAs | Open Reading Frames | Proteins | RNA-Binding Proteins | Transcription Factors | Transcription, Genetic
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A biomedical and genomic research center that is independently governed that encompasses three types of organizational units: core member laboratories, programs and platforms which work together and with other collaborators to tackle critical problems in human biology and disease. Data and cutting edge software tools are generated and developed, and these tools analyze those data (increasingly large genome-related datasets) which is shared openly with the scientific community. The Broad faculty includes core members and associate members. All associate members hold primary appointments in a home department at one of the partner institutions, but are deeply involved in the scientific work and culture of the Broad Institute. It is formally affiliated with the Massachusetts Institute of Technology, Harvard University and its affiliated hospitals.
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