Opposing microRNA families regulate self-renewal in mouse embryonic stem cells.
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.
Melton
Collin
C
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Program in Biomedical Sciences, University of California San Francisco, San Francisco, California 94143, USA.
Judson
Robert L
RL
Blelloch
Robert
R
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000235:genetics; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D020868:Gene Silencing; D016259:Genes, myc / Q000235:genetics; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C474044:Dgcr8 protein, mouse; C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D011506:Proteins; D016601:RNA-Binding Proteins; C509167:Sall4 protein, mouse; D014157:Transcription Factors; C542687:mirnlet7 microRNA, mouse