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Molecular and Cellular Biology, March 2005, p. 2475-2485, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2475-2485.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Octamer and Sox Elements Are Required for Transcriptional cis Regulation of Nanog Gene Expression

Takao Kuroda,1 Masako Tada,1,2 Hiroshi Kubota,3 Hironobu Kimura,1 Shin-ya Hatano,1 Hirofumi Suemori,4 Norio Nakatsuji,1 and Takashi Tada5*

Department of Development and Differentiation,1 Department of Molecular and Cellular Biology,3 Laboratory of Embryonic Stem Cell Research,4 Laboratory of Stem Cell Engineering, Institute for Frontier Medical Sciences, Kyoto University, Shogoin, Sakyo-ku, Kyoto,5 ReproCELL Inc., Chiyoda-ku, Tokyo, Japan2

Received 14 July 2004/ Returned for modification 26 August 2004/ Accepted 7 December 2004

The pluripotential cell-specific gene Nanog encodes a homeodomain-bearing transcription factor required for maintaining the undifferentiated state of stem cells. However, the molecular mechanisms that regulate Nanog gene expression are largely unknown. To address this important issue, we used luciferase assays to monitor the relative activities of deletion fragments from the 5'-flanking region of the gene. An adjacent pair of highly conserved Octamer- and Sox-binding sites was found to be essential for activating pluripotential state-specific gene expression. Furthermore, the 5'-end fragment encompassing the Octamer/Sox element was sufficient for inducing the proper expression of a green fluorescent protein reporter gene even in human embryonic stem (ES) cells. The potential of OCT4 and SOX2 to bind to this element was verified by electrophoretic mobility shift assays with extracts from F9 embryonal carcinoma cells and embryonic germ cells derived from embryonic day 12.5 embryos. However, in ES cell extracts, a complex of OCT4 with an undefined factor preferentially bound to the Octamer/Sox element. Thus, Nanog transcription may be regulated through an interaction between Oct4 and Sox2 or a novel pluripotential cell-specific Sox element-binding factor which is prominent in ES cells.

* Corresponding author. Mailing address: Takashi Tada Laboratory of Stem Cell Engineering, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3823. Fax: 81-75-751-3890. E-mail: ttada{at}frontier.kyoto-u.ac.jp.

Molecular and Cellular Biology, March 2005, p. 2475-2485, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2475-2485.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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