Abstract
Polycomb group (PcG) proteins play important roles in repressing lineage-specific genes and maintaining the undifferentiated state of mouse embryonic stem cells (mESCs). However, how PcG proteins are recruited to their target genes is largely unknown. Here, we show that the H3K36-specific histone demethylase Kdm2b is highly expressed in mESCs and regulated by the pluripotent factors Oct4 and Sox2 directly. Depletion of Kdm2b in mESCs causes de-repression of lineage-specific genes and induces early differentiation. The function of Kdm2b depends on its CxxC-ZF domain, which mediates its genome-wide binding to CpG islands (CGIs). Kdm2b interacts with the core components of polycomb repressive complex 1 (PRC1) and recruits the complex to the CGIs of early lineage-specific genes. Thus, our study not only reveals an Oct4-Sox2-Kdm2b-PRC1-CGI regulatory axis and its function in maintaining the undifferentiated state of mESCs, but also demonstrates a critical function of Kdm2b in recruiting PRC1 to the CGIs of lineage-specific genes to repress their expression.
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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Animals
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Base Sequence
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Cell Differentiation*
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Cell Lineage
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Cell Proliferation
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Cells, Cultured
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Chromatin Immunoprecipitation
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CpG Islands / genetics*
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DNA Methylation
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Electrophoretic Mobility Shift Assay
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / physiology*
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F-Box Proteins / antagonists & inhibitors
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Gene Expression Regulation, Developmental*
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Genes, Developmental*
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Genome
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Immunoprecipitation
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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Luciferases / metabolism
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Mice
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Molecular Sequence Data
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Oligonucleotide Array Sequence Analysis
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / physiology
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Polycomb Repressive Complex 1 / genetics
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Polycomb Repressive Complex 1 / metabolism*
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Sequence Homology, Nucleic Acid
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Transfection
Substances
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Biomarkers, Tumor
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F-Box Proteins
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Octamer Transcription Factor-3
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Pou5f1 protein, mouse
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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SOXB1 Transcription Factors
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Sox2 protein, mouse
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Luciferases
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Jumonji Domain-Containing Histone Demethylases
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Kdm2b protein, mouse
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Polycomb Repressive Complex 1