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Mol. Cell. Biol. doi:10.1128/MCB.00359-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Oct4/Sox2-Regulated miR-302 Targets Cyclin D1 in Human ESC

Chromatin and Gene Expression Section, Laboratory of Molecular Carcinogenesis, Biostatistics Branch, Molecular Developmental Biology Group, Laboratory of Reproductive & Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA

^* To whom correspondence should be addressed. Email: archer1{at}niehs.nih.gov.

	Abstract

Oct4 and Sox2 are transcription factors required for pluripotency during early embryogenesis and maintenance of embryonic stem cell (ESC) identity. Functional mechanisms contributing to pluripotency are expected to be associated with genes transcriptionally activated by these factors. Here, we show that Oct4 and Sox2 bind to a conserved promoter region of miR-302, a cluster of eight miRNAs expressed specifically in ESCs and pluripotent cells. Expression of miR-302a is dependent on Oct4/Sox2 in human ESCs, and miR-302a is expressed at the same developmental stages and in the same tissues as Oct4 during embryogenesis. MiR-302a is predicted to target many cell cycle regulators, and expression of miR-302a in primary and transformed cell lines promotes an increase in S phase and a decrease in G1 phase cells, reminiscent of an ESC-like cell cycle profile. Correspondingly, inhibition of miR-302 causes hESCs to accumulate in G1 phase. Moreover, we show that miR-302a represses the productive translation of an important G1 regulator, Cyclin D1, in human ESCs. Transcriptional activation of miR-302 and translational repression of its targets, such as Cyclin D1, may provide a link between Oct4/Sox2 and cell cycle regulation in pluripotent cells.

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