The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes.
The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes.
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DOI：
10.1093/nar/gkac258
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发表时间：
2022-05-06
影响因子：
14.9
通讯作者：
Jenner, Richard G.
中科院分区：
文献类型：
--
作者：
Hertweck, Arnulf;Vila de Mucha, Maria;Barber, Paul R.;Dagil, Robert;Porter, Hayley;Ramos, Andres;Lord, Graham M.;Jenner, Richard G.
谱系决定转录因子(LD-TF)驱动祖细胞分化为特定的谱系。在CD4+T细胞中，T-bet决定TH1谱系的分化，而GATA3则驱动另一种TH2谱系的分化。然而，LD-TF，包括T-bet和GATA3，经常是共表达的，但这如何影响LD-TF功能尚不清楚。通过在小鼠T细胞中单独或联合表达T-bet和GATA3，我们发现T-bet在其靶点隔离了GATA3，从而从TH2基因中去除了GATA3。GATA3的这种重新分布不依赖于GATA3DNA结合活性，而是由T-bet DNA结合域介导，它与GATA3DNA结合域相互作用，改变GATA3的S序列结合偏好。这一机制允许T-bet在GATA3存在的情况下驱动TH1基因表达程序。我们认为，一个LD-TF由另一个LD-TF的重新分配可能是一种常见的机制，可以解释为什么即使在其他转录因子驱动替代分化途径的情况下，也可以做出特定的细胞命运选择。
Lineage-determining transcription factors (LD-TFs) drive the differentiation of progenitor cells into a specific lineage. In CD4+ T cells, T-bet dictates differentiation of the TH1 lineage, whereas GATA3 drives differentiation of the alternative TH2 lineage. However, LD-TFs, including T-bet and GATA3, are frequently co-expressed but how this affects LD-TF function is not known. By expressing T-bet and GATA3 separately or together in mouse T cells, we show that T-bet sequesters GATA3 at its target sites, thereby removing GATA3 from TH2 genes. This redistribution of GATA3 is independent of GATA3 DNA binding activity and is instead mediated by the T-bet DNA binding domain, which interacts with the GATA3 DNA binding domain and changes GATA3′s sequence binding preference. This mechanism allows T-bet to drive the TH1 gene expression program in the presence of GATA3. We propose that redistribution of one LD-TF by another may be a common mechanism that could explain how specific cell fate choices can be made even in the presence of other transcription factors driving alternative differentiation pathways.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
4
作者：
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Jenner RG
DOI：
10.1084/jem.20170494
发表时间：
2017-07-03
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Fang D;Zhu J
通讯作者：
Zhu J
DOI：
10.12703/r/10-30
发表时间：
2021
期刊：
Faculty reviews
影响因子：
--
作者：
Butcher MJ;Zhu J
通讯作者：
Zhu J
DOI：
10.1084/jem.20171127
发表时间：
2018-05-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fang D;Cui K;Hu G;Gurram RK;Zhong C;Oler AJ;Yagi R;Zhao M;Sharma S;Liu P;Sun B;Zhao K;Zhu J
通讯作者：
Zhu J