The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells.
After antigen encounter by CD4(+) T cells, polarizing cytokines induce the expression of master regulators that control differentiation. Inactivation of the histone methyltransferase Ezh2 was found to specifically enhance T helper 1 (Th1) and Th2 cell differentiation and plasticity. Ezh2 directly bound and facilitated correct expression of Tbx21 and Gata3 in differentiating Th1 and Th2 cells, accompanied by substantial trimethylation at lysine 27 of histone 3 (H3K27me3). In addition, Ezh2 deficiency resulted in spontaneous generation of discrete IFN-γ and Th2 cytokine-producing populations in nonpolarizing cultures, and under these conditions IFN-γ expression was largely dependent on enhanced expression of the transcription factor Eomesodermin. In vivo, loss of Ezh2 caused increased pathology in a model of allergic asthma and resulted in progressive accumulation of memory phenotype Th2 cells. This study establishes a functional link between Ezh2 and transcriptional regulation of lineage-specifying genes in terminally differentiated CD4(+) T cells.
Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Damon J
DJ
Tumes
Atsushi
A
Onodera
Akane
A
Suzuki
Kenta
K
Shinoda
Yusuke
Y
Endo
Chiaki
C
Iwamura
Hiroyuki
H
Hosokawa
Haruhiko
H
Koseki
Koji
K
Tokoyoda
Yutaka
Y
Suzuki
Shinichiro
S
Motohashi
Toshinori
T
Nakayama
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D007156:Immunologic Memory; D059425:Interferon-gamma Release Tests; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017384:Sequence Deletion; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology; D000098815:T-bet Transcription Factor
C491198:Eomes protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006657:Histones; D008222:Lymphokines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000076983:Histone Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2