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Molecular and Cellular Biology, October 2006, p. 7772-7782, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00468-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Klf4 Cooperates with Oct3/4 and Sox2 To Activate the Lefty1 Core Promoter in Embryonic Stem Cells{triangledown}

Yuhki Nakatake,1 Nobutaka Fukui,1,2,3 Yuko Iwamatsu,1 Shinji Masui,1 Kadue Takahashi,1 Rika Yagi,1 Kiyohito Yagi,2 Jun-ichi Miyazaki,3 Ryo Matoba,4 Minoru S. H. Ko,4 and Hitoshi Niwa1,5*

Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology (CDB), Minatojima-Minamimachi 2-2-3, Chuo-ku, Kobe 650-0047, Japan,1 Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita C., Osaka 565-0871, Japan,2 Stem Cell Regulation Research, Area of Molecular Therapeutics, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita C., Osaka 565-0871, Japan,3 Developmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224,4 Laboratory for Development and Regenerative Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan5

Received 17 March 2006/ Returned for modification 2 May 2006/ Accepted 15 August 2006

Although the POU transcription factor Oct3/4 is pivotal in maintaining self renewal of embryonic stem (ES) cells, little is known of its molecular mechanisms. We previously reported that the N-terminal transactivation domain of Oct3/4 is required for activation of Lefty1 expression (H. Niwa, S. Masui, I. Chambers, A. G. Smith, and J. Miyazaki, Mol. Cell. Biol. 22:1526-1536, 2002). Here we test whether Lefty1 is a direct target of Oct3/4. We identified an ES cell-specific enhancer upstream of the Lefty1 promoter that contains binding sites for Oct3/4 and Sox2. Unlike other known Oct3/4-Sox2-dependent enhancers, however, this enhancer element could not be activated by Oct3/4 and Sox2 in differentiated cells. By functional screening of ES-specific transcription factors, we found that Krüppel-like factor 4 (Klf4) cooperates with Oct3/4 and Sox2 to activate Lefty1 expression, and that Klf4 acts as a mediating factor that specifically binds to the proximal element of the Lefty1 promoter. DNA microarray analysis revealed that a subset of putative Oct3/4 target genes may be regulated in the same manner. Our findings shed light on a novel function of Oct3/4 in ES cells.

* Corresponding author. Mailing address: Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Minatojima-Minamimachi 2-2-3, Chu-o-ku, Kobe 650-0047, Japan. Phone: 81-78-306-1927. Fax: 81-78-306-1929. E-mail: niwa{at}cdb.riken.jp.

{triangledown} Published ahead of print on 5 September 2006.

Molecular and Cellular Biology, October 2006, p. 7772-7782, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00468-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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