Abstract
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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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Cell Differentiation
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Conserved Sequence
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Gene Expression / genetics
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Genes, Reporter / genetics
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HMGB Proteins / genetics
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HMGB Proteins / metabolism*
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Humans
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism*
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Left-Right Determination Factors
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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Organic Cation Transport Proteins / genetics
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Organic Cation Transport Proteins / metabolism*
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Promoter Regions, Genetic / genetics*
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Protein Binding
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Sex-Determining Region Y Protein / genetics
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Sex-Determining Region Y Protein / metabolism*
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Stem Cells / cytology
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Stem Cells / metabolism*
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Transforming Growth Factor beta / genetics*
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Transforming Growth Factor beta / metabolism
Substances
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HMGB Proteins
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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Left-Right Determination Factors
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Lefty1 protein, mouse
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Membrane Proteins
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Organic Cation Transport Proteins
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Sex-Determining Region Y Protein
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Transforming Growth Factor beta