Klf4 cooperates with Oct3/4 and Sox2 to activate the Lefty1 core promoter in embryonic stem cells.
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.
Nakatake
Yuhki
Y
Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Minatojima-Minamimachi 2-2-3, Chu-o-ku, Kobe 650-0047, Japan.
Fukui
Nobutaka
N
Iwamatsu
Yuko
Y
Masui
Shinji
S
Takahashi
Kadue
K
Yagi
Rika
R
Yagi
Kiyohito
K
Miyazaki
Jun-Ichi
J
Matoba
Ryo
R
Ko
Minoru S H
MS
Niwa
Hitoshi
H
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D017124:Conserved Sequence; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055458:Left-Right Determination Factors; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D024002:HMGB Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D055458:Left-Right Determination Factors; C111386:Lefty1 protein, mouse; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; D051876:Sex-Determining Region Y Protein; D016212:Transforming Growth Factor beta