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Nature 463, 621-626 (4 February 2010) | doi:10.1038/nature08725, n5 d# q6 T5 G
$ F! O& Q& n- X+ }* pOpposing microRNA families regulate self-renewal in mouse embryonic stem cells' b4 k7 B6 n' k/ q; M
" X" F. V9 v4 h+ \Collin Melton1,2, Robert L. Judson1,2 & Robert Blelloch1,2
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+ Q8 W5 t; Q& z# ~1 The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Program in Biomedical Sciences,. K2 e, J6 z" v8 H; ^
2 Department of Urology, University of California San Francisco, San Francisco, California 94143, USA. w% v. E5 C5 d6 j) q F+ G
) t5 I2 g# W6 J3 r: ^8 E% g/ ^* N% GWhen 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. |
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发表于 2010-2-4 11:13
发表于 2010-2-4 12:56
