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EMBRYONIC STEM CELLS |
1 Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore
2 Bioinformatics Institute, Singapore
3 Information and Mathematical Sciences, Genome Institute of Singapore, Singapore
4 ISIS Pharmaceuticals, Carlsbad, CA, USA
5 Bioinformatics and Pattern Discovery Group, IBM Thomas J Watson Research Center, NY, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Boston, MA, USA;
6 Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore; Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: limb1{at}gis.a-star.edu.sg.
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Abstract |
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Hundreds of microRNAs (miRNAs) are expressed in mammalian cells where they aid in modulating gene expression by mediating mRNA transcript cleavage and/or regulation of translation rate. Functional studies to date have demonstrated that several of these miRNAs are important during development. However, the role of miRNAs in the regulation of stem cell growth and differentiation is not well understood. We show herein, that miRNA (miR)-134 levels are maximally elevated at day 4 post-retinoic acid (RA)- or day 2 N2B27- induced differentiation of mouse embryonic stem cells (mESCs), but this change is not observed during embryoid body differentiation. The elevation of miR-134 levels alone in mESCs enhances differentiation towards ectodermal lineages, an effect that is blocked by a miR-134 antagonist. The promotion of mESC differentiation by miR-134 is due, in part, to its direct translational attenuation of Nanog and LRH1, both of which are known positive regulators of Oct4/POU5F1 and mESC growth. Together, the data demonstrate that miR-134 alone can enhance the differentiation of mESCs to ectodermal lineages and establish a functional role for miR-134 in modulating mESC differentiation through its potential to target and regulate multiple mRNAs.
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Y. M.-S. Tay, W.-.L. Tam, and Y.-S. Ang contributed equally to this work. I. Rigoutsos, A. Thomson, and B. Lim are co-senior authors.
Key Words. Embryonic stem cells, microRNAs, cell differentiation, retinoic acid
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