T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes.
Naïve T cells differentiate into effector cells upon stimulation with antigen, a process that is accompanied by changes in the chromatin structure of effector cytokine genes. Using histone acetylation to evaluate these changes, we showed that T cell receptor (TCR) stimulation results in early activation of the genes encoding both interleukin 4 and interferon-gamma. We found that continued culture in the presence of polarizing cytokines established a selective pattern of histone acetylation on both cytokine genes; this correlated with restricted access of the transcription factor NFAT1 to these gene regulatory regions as well as mutually exclusive gene expression by the differentiated T cells. Our data point to a biphasic process in which cytokine-driven signaling pathways maintain and reinforce chromatin structural changes initiated by the TCR. This process ensures that cytokine genes remain accessible to the relevant transcription factors and promotes functional cooperation of the inducible transcription factor NFAT with lineage-specific transcription factors such as GATA-3 and T-bet.
Avni
Orly
O
The Center for Blood Research and the Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Lee
Dong
D
Macian
Fernando
F
Szabo
Susanne J
SJ
Glimcher
Laurie H
LH
Rao
Anjana
A
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D050990:GATA3 Transcription Factor; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics*; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology* / Q000502:physiology; D018418:Th2 Cells / Q000166:cytology* / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; D006657:Histones; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma