Abstract
The pluripotency-determining gene Oct3/4 (also called Pou5f1) undergoes postimplantation silencing in a process mediated by the histone methyltransferase G9a. Microarray analysis now shows that this enzyme may operate as a master regulator that inactivates numerous early-embryonic genes by bringing about heterochromatinization of methylated histone H3K9 and de novo DNA methylation. Genetic studies in differentiating embryonic stem cells demonstrate that a point mutation in the G9a SET domain prevents heterochromatinization but still allows de novo methylation, whereas biochemical and functional studies indicate that G9a itself is capable of bringing about de novo methylation through its ankyrin domain, by recruiting Dnmt3a and Dnmt3b independently of its histone methyltransferase activity. These modifications seem to be programmed for carrying out two separate biological functions: histone methylation blocks target-gene reactivation in the absence of transcriptional repressors, whereas DNA methylation prevents reprogramming to the undifferentiated state.
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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Cell Line
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation*
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DNA Methyltransferase 3A
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DNA Methyltransferase 3B
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Embryo, Mammalian / physiology*
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / physiology*
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Epigenesis, Genetic
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Developmental
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Gene Silencing*
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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Histones / metabolism
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Humans
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Mice
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Mice, Transgenic
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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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Protein Methyltransferases / metabolism*
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Protein Structure, Tertiary
Substances
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DNMT3A protein, human
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Dnmt3a protein, mouse
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Histones
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Octamer Transcription Factor-3
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Pou5f1 protein, mouse
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Histone Methyltransferases
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Protein Methyltransferases
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A
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Histone-Lysine N-Methyltransferase