Abstract
In embryonic stem cells (ESCs), Wnt-responsive development-related genes are silenced to maintain pluripotency and their expression is activated during differentiation. Acetylation of histones by histone acetyltransferases stimulates transcription, whereas deacetylation of histones by HDACs is correlated with transcriptional repression. Although Wnt-mediated gene transcription has been intimately linked to the acetylation or deacetylation of histones, how Wnt signaling regulates this type of histone modification is poorly understood. Here, we report that Smek, a regulatory subunit of protein phosphatase 4 (PP4) complex, plays an important role in histone deacetylation and silencing of the Wnt-responsive gene, brachyury, in ESCs. Smek mediates recruitment of PP4c and HDAC1 to the Tcf/Lef binding site of the brachyury promoter and inhibits brachyury expression in ESCs. Activation of Wnt signaling during differentiation causes disruption of the Smek/PP4c/HDAC1 complex, resulting in an increase in histones H3 and H4 acetylation at the brachyury gene locus. These results suggest that the Smek-containing PP4 complex represses transcription of Wnt-responsive development-related genes through histone deacetylation, and that this complex is essential for ESC pluripotency maintenance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Alkaline Phosphatase / metabolism
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Animals
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Cell Differentiation / genetics
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Cell Nucleus / metabolism
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Cells, Cultured
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Down-Regulation
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Fetal Proteins / genetics*
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Fetal Proteins / metabolism
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Gene Expression Regulation
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Goosecoid Protein / genetics
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Goosecoid Protein / metabolism
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Histone Deacetylase 1 / metabolism
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Histones / metabolism*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Immunoprecipitation
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LIM-Homeodomain Proteins
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Mice
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Multiprotein Complexes / metabolism
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Pluripotent Stem Cells / metabolism*
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Promoter Regions, Genetic
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Protein Binding
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RNA Interference
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T-Box Domain Proteins / genetics*
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T-Box Domain Proteins / metabolism
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Transcription Factors
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Transcription, Genetic
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Fetal Proteins
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Goosecoid Protein
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Gsc protein, mouse
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Histones
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Homeodomain Proteins
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LIM-Homeodomain Proteins
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Multiprotein Complexes
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T-Box Domain Proteins
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Transcription Factors
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Wnt Proteins
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beta Catenin
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insulin gene enhancer binding protein Isl-1
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Vascular Endothelial Growth Factor Receptor-2
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Alkaline Phosphatase
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Phosphoprotein Phosphatases
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Ppp4r3a protein, mouse
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Smek2 protein, mouse
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Hdac1 protein, mouse
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Histone Deacetylase 1
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Brachyury protein