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Molecular and Cellular Biology, July 2005, p. 6031-6046, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6031-6046.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Reciprocal Transcriptional Regulation of Pou5f1 and Sox2 via the Oct4/Sox2 Complex in Embryonic Stem Cells

Joon-Lin Chew,1,2,{dagger} Yuin-Han Loh,1,2,{dagger} Wensheng Zhang,2,{dagger} Xi Chen,1,2 Wai-Leong Tam,3 Leng-Siew Yeap,3 Pin Li,3 Yen-Sin Ang,3 Bing Lim,3,4 Paul Robson,1,3 and Huck-Hui Ng1,2*

Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore,1 Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672, Singapore,2 Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore 138672, Singapore;,3 Harvard Institutes of Medicine, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts4

Received 7 December 2004/ Returned for modification 12 January 2005/ Accepted 21 April 2005

Embryonic stem cells (ESCs) are pluripotent cells that can either self-renew or differentiate into many cell types. Oct4 and Sox2 are transcription factors essential to the pluripotent and self-renewing phenotypes of ESCs. Both factors are upstream in the hierarchy of the transcription regulatory network and are partners in regulating several ESC-specific genes. In ESCs, Sox2 is transcriptionally regulated by an enhancer containing a composite sox-oct element that Oct4 and Sox2 bind in a combinatorial interaction. It has previously been shown that Pou5f1, the Oct4 gene, contains a distal enhancer imparting specific expression in both ESCs and preimplantation embryos. Here, we identify a composite sox-oct element within this enhancer and show that it is involved in Pou5f1 transcriptional activity in ESCs. In vitro experiments with ESC nuclear extracts demonstrate that Oct4 and Sox2 interact specifically with this regulatory element. More importantly, by chromatin immunoprecipitation assay, we establish that both Oct4 and Sox2 bind directly to the composite sox-oct elements in both Pou5f1 and Sox2 in living mouse and human ESCs. Specific knockdown of either Oct4 or Sox2 by RNA interference leads to the reduction of both genes' enhancer activities and endogenous expression levels in addition to ESC differentiation. Our data uncover a positive and potentially self-reinforcing regulatory loop that maintains Pou5f1 and Sox2 expression via the Oct4/Sox2 complex in pluripotent cells.

* Corresponding author. Mailing address: Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore 138672, Singapore. Phone: (65) 6478 8145. Fax: (65) 6478 9004. E-mail: nghh{at}gis.a-star.edu.sg.

{dagger} J.-L.C., Y.-H.L., and W.Z. contributed equally to this work.

Molecular and Cellular Biology, July 2005, p. 6031-6046, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6031-6046.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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