Polycomb Antagonizes p300/CREB-binding Protein-associated Factor to Silence FOXP3 in a Kruppel-like Factor-dependent Manner |
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| Authors: | Yuning Xiong Sahil Khanna Adrienne L. Grzenda Olga F. Sarmento Phyllis A. Svingen Gwen A. Lomberk Raul A. Urrutia William A. Faubion Jr. |
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| Affiliation: | From the ‡Chromatin Dynamics and Epigenetics Laboratory.;the Departments of ¶Molecular Biology and ;‖Immunology, and ;the §Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 |
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| 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. |
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| Keywords: | Epigenetics Histone Modification Kruppel-like Factor (KLF) Polycomb T Cell Biology FOXP3 T Regulatory Cell |
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