Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells.
Cell differentiation involves activation and silencing of lineage-specific genes. Here we show that the transcription factor Runx3 is induced in T helper type 1 (T(H)1) cells in a T-bet-dependent manner, and that both transcription factors T-bet and Runx3 are required for maximal production of interferon-gamma (IFN-gamma) and silencing of the gene encoding interleukin 4 (Il4) in T(H)1 cells. T-bet does not repress Il4 in Runx3-deficient T(H)2 cells, but coexpression of Runx3 and T-bet induces potent repression in those cells. Both T-bet and Runx3 bind to the Ifng promoter and the Il4 silencer, and deletion of the silencer decreases the sensitivity of Il4 to repression by either factor. Our data indicate that cytokine gene expression in T(H)1 cells may be controlled by a feed-forward regulatory circuit in which T-bet induces Runx3 and then 'partners' with Runx3 to direct lineage-specific gene activation and silencing.
Djuretic
Ivana M
IM
Harvard Medical School and the CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA.
Levanon
Ditsa
D
Negreanu
Varda
V
Groner
Yoram
Y
Rao
Anjana
A
Ansel
K Mark
KM
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*; D015533:Transcriptional Activation; D000098815:T-bet Transcription Factor
D050677:Core Binding Factor Alpha 3 Subunit; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma