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Abstract
Oct4 and Sox2 are transcription factors required for pluripotency during early embryogenesis and for the 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 microRNAs expressed specifically in ESCs and pluripotent cells. The expression of miR-302a is dependent on Oct4/Sox2 in human ESCs (hESCs), 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 the 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, the 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 hESCs. The transcriptional activation of miR-302 and the translational repression of its targets, such as cyclin D1, may provide a link between Oct4/Sox2 and cell cycle regulation in pluripotent cells.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We thank Lois Annab for maintenance of MEFs; Paul Wade, Sayura Aoyagi, and Jeff Card for helpful discussion; Gina Goulding and Trisha Castriano for assistance with mouse embryology; Ajeet Singh for mouse embryonic samples; Julie Foley for assistance with immunohistochemistry; Grace Kissling for assistance with statistical analysis; and Carl Bortner and Maria Sifre for assistance with flow cytometry.
This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH, project number Z01 ES071006-09.