Abstract
Inducible gene expression underlies the epigenetically inherited differentiation program of most immune cells. We report that the promoter of the FOXP3 gene possesses two distinct functional states: an "off state" mediated by the polycomb histone methyltransferase complex and a histone acetyltransferase-dependent "on state." Regulating these states is the presence of a Kruppel-like factor (KLF)-containing Polycomb response element. In the KLF10(-/-) mouse, the FOXP3 promoter is epigenetically silenced by EZH2 (Enhancer of Zeste 2)-mediated trimethylation of Histone 3 K27; thus, impaired FOXP3 induction and inappropriate adaptive T regulatory cell differentiation results in vitro and in vivo. The epigenetic transmittance of adaptive T regulatory cell deficiency is demonstrated throughout more than 40 generations of mice. These results provide insight into chromatin remodeling events key to phenotypic features of distinct T cell populations.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Chromatin Assembly and Disassembly / physiology
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Early Growth Response Transcription Factors / biosynthesis*
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Early Growth Response Transcription Factors / genetics
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Early Growth Response Transcription Factors / immunology
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Enhancer of Zeste Homolog 2 Protein
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Forkhead Transcription Factors / biosynthesis*
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Gene Silencing / physiology*
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Kruppel-Like Transcription Factors / biosynthesis*
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / immunology
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Male
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Mice
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Mice, Knockout
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / immunology
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Polycomb Repressive Complex 2 / metabolism
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Polycomb-Group Proteins / genetics
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Polycomb-Group Proteins / immunology
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Polycomb-Group Proteins / metabolism*
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Response Elements / physiology*
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism*
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p300-CBP Transcription Factors / antagonists & inhibitors
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p300-CBP Transcription Factors / genetics
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p300-CBP Transcription Factors / immunology
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p300-CBP Transcription Factors / metabolism*
Substances
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Early Growth Response Transcription Factors
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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KLF10 protein, mouse
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Kruppel-Like Transcription Factors
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Polycomb-Group Proteins
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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Polycomb Repressive Complex 2
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p300-CBP Transcription Factors
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p300-CBP-associated factor