Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells.
Multipotential naive CD4(+) T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4(+) T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naive, Th1, Th2, Th17, iTreg, and natural Treg (nTreg) cells. We found that although modifications of signature-cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, genes encoding transcription factors like Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and interferon-gamma induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4(+) T helper cell differentiation.
Wei
Gang
G
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wei
Lai
L
Zhu
Jinfang
J
Zang
Chongzhi
C
Hu-Li
Jane
J
Yao
Zhengju
Z
Cui
Kairong
K
Kanno
Yuka
Y
Roh
Tae-Young
TY
Watford
Wendy T
WT
Schones
Dustin E
DE
Peng
Weiqun
W
Sun
Hong-Wei
HW
Paul
William E
WE
O'Shea
John J
JJ
Zhao
Keji
K
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins; D006657:Histones / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D008810:Mice, Inbred C57BL; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000276:immunology; D046188:Protein Modification, Translational; D056485:Retinoblastoma-Binding Protein 2; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse; D056485:Retinoblastoma-Binding Protein 2; C523761:Kdm6b protein, mouse; D010089:Oxidoreductases, N-Demethylating