Polycomb antagonizes p300/CREB-binding protein-associated factor to silence FOXP3 in a Kruppel-like factor-dependent manner.
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.
Chromatin Dynamics and Epigenetics Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA.
Yuning
Y
Xiong
Sahil
S
Khanna
Adrienne L
AL
Grzenda
Olga F
OF
Sarmento
Phyllis A
PA
Svingen
Gwen A
GA
Lomberk
Raul A
RA
Urrutia
William A
WA
Faubion
D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D051765:Early Growth Response Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D000071221:Enhancer of Zeste Homolog 2 Protein; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D051765:Early Growth Response Transcription Factors; D000071221:Enhancer of Zeste Homolog 2 Protein; D051858:Forkhead Transcription Factors; D051741:Kruppel-Like Transcription Factors; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C498833:Foxp3 protein, mouse; C569958:KLF10 protein, mouse; C498410:Ezh2 protein, mouse