Abstract
Transcriptional control of stem cell genes is a critical step in differentiation of embryonic stem cells and in reprogramming of somatic cells into stem cells. Here we report that Lsh, a regulator of repressive chromatin at retrotransposons, also plays an important role in silencing of stem cell-specific genes such as Oct4. We found that CpG methylation is gained during in vitro differentiation of several stem cell-specific genes (in 11 of 12 promoter regions) and thus appears to be a common epigenetic mark. Lsh depletion prevents complete silencing of stem cell gene expression and moreover promotes the maintenance of stem cell characteristics in culture. Lsh is required for establishment of DNA methylation patterns at stem cell genes during differentiation, in part by regulating access of Dnmt3b to its genomic targets. Our results indicate that Lsh is involved in the control of stem cell genes and suggest that Lsh is an important epigenetic modulator during early stem cell differentiation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Blotting, Southern
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Blotting, Western
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cell Line
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Chromosomal Proteins, Non-Histone
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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DNA Methylation*
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DNA Methyltransferase 3B
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Epidermal Growth Factor / genetics
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Gene Silencing*
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Growth Differentiation Factor 3 / genetics
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Homeodomain Proteins / genetics
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Membrane Glycoproteins / genetics
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Mice
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Nanog Homeobox Protein
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Neoplasm Proteins / genetics
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Octamer Transcription Factor-3 / genetics
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Polymerase Chain Reaction
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Promoter Regions, Genetic / genetics
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Protein Binding
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Repressor Proteins / genetics
Substances
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Chromosomal Proteins, Non-Histone
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Dppa3 protein, mouse
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Gdf3 protein, mouse
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Growth Differentiation Factor 3
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Homeodomain Proteins
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Membrane Glycoproteins
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Nanog Homeobox Protein
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Nanog protein, mouse
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Neoplasm Proteins
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Octamer Transcription Factor-3
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Pou5f1 protein, mouse
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Repressor Proteins
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Tdgf1 protein, mouse
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Epidermal Growth Factor
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DNA (Cytosine-5-)-Methyltransferases
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DNA Helicases
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lymphoid specific helicase, mouse