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Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells.

Abstract 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.
PMID
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Authors

Mayor MeshTerms

Gene Expression Regulation

Keywords
Journal Title nature immunology
Publication Year Start




PMID- 17195845
OWN - NLM
STAT- MEDLINE
DCOM- 20070330
LR  - 20081121
IS  - 1529-2908 (Print)
IS  - 1529-2908 (Linking)
VI  - 8
IP  - 2
DP  - 2007 Feb
TI  - Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 
      in T helper type 1 cells.
PG  - 145-53
AB  - 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.
FAU - Djuretic, Ivana M
AU  - Djuretic IM
AD  - Harvard Medical School and the CBR Institute for Biomedical Research, Boston,
      Massachusetts 02115, USA.
FAU - Levanon, Ditsa
AU  - Levanon D
FAU - Negreanu, Varda
AU  - Negreanu V
FAU - Groner, Yoram
AU  - Groner Y
FAU - Rao, Anjana
AU  - Rao A
FAU - Ansel, K Mark
AU  - Ansel KM
LA  - eng
GR  - AI144432/AI/NIAID NIH HHS/United States
GR  - HL67664/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20061231
PL  - United States
TA  - Nat Immunol
JT  - Nature immunology
JID - 100941354
RN  - 0 (Core Binding Factor Alpha 3 Subunit)
RN  - 0 (T-Box Domain Proteins)
RN  - 0 (T-box transcription factor TBX21)
RN  - 207137-56-2 (Interleukin-4)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
CIN - Nat Immunol. 2007 Feb;8(2):119-20. PMID: 17242680
MH  - Animals
MH  - Base Sequence
MH  - Cells, Cultured
MH  - Core Binding Factor Alpha 3 Subunit/deficiency/genetics/*metabolism
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Interferon-gamma/genetics/*metabolism
MH  - Interleukin-4/biosynthesis/*genetics
MH  - Mice
MH  - Molecular Sequence Data
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Binding
MH  - T-Box Domain Proteins/deficiency/genetics/*metabolism
MH  - Th1 Cells/*metabolism
MH  - Transcriptional Activation
EDAT- 2007/01/02 09:00
MHDA- 2007/03/31 09:00
CRDT- 2007/01/02 09:00
PHST- 2006/07/31 00:00 [received]
PHST- 2006/11/14 00:00 [accepted]
PHST- 2007/01/02 09:00 [pubmed]
PHST- 2007/03/31 09:00 [medline]
PHST- 2007/01/02 09:00 [entrez]
AID - ni1424 [pii]
AID - 10.1038/ni1424 [doi]
PST - ppublish
SO  - Nat Immunol. 2007 Feb;8(2):145-53. doi: 10.1038/ni1424. Epub 2006 Dec 31.