The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes
The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes
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DOI：
10.1073/pnas.0909357106
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发表时间：
2009-10-20
影响因子：
11.1
通讯作者：
Lord, Graham M.
中科院分区：
文献类型：
--
作者：
Jenner, Richard G.;Townsend, Michael J.;Lord, Graham M.
在检测到抗原后，CD4(+)T辅助(Th)细胞可以分化为多种效应器类型，以适应不同病原体的免疫反应。可供选择的Th1和Th2细胞命运分别由转录因子T-bet和GATA-3决定。由于这两个因素只有少数几个靶基因已知，因此，T-bet和GATA-3诱导分化为不同细胞命运的机制还不完全清楚。在这里，我们提供了原代人类T细胞中T-bet和GATA-3结合的基因组图谱，并确定了它们的目标基因，其中大部分是以前未知的。在Th1细胞中，T-bet与多种功能基因相关联，包括那些在转录调控、趋化和黏附中起作用的基因。GATA-3在Th1和Th2细胞中都占有基因，出人意料的是，它与T-bet有很大比例的共同靶点。T-bet的重新互补改变了这些基因的表达，反映了它们在Th1和Th2谱系之间的差异表达。这些数据表明，在Th1和Th2谱系承诺之间的选择是T-bet和GATA-3在一组共同的靶基因上相反作用的结果，并可能为谱系特定的转录因子之间的相互作用提供一个通用的范例。
Upon detection of antigen, CD4(+) T helper (Th) cells can differentiate into a number of effector types that tailor the immune response to different pathogens. Alternative Th1 and Th2 cell fates are specified by the transcription factors T-bet and GATA-3, respectively. Only a handful of target genes are known for these two factors and because of this, the mechanism through which T-bet and GATA-3 induce differentiation toward alternative cell fates is not fully understood. Here, we provide a genomic map of T-bet and GATA-3 binding in primary human T cells and identify their target genes, most of which are previously unknown. In Th1 cells, T-bet associates with genes of diverse function, including those with roles in transcriptional regulation, chemotaxis and adhesion. GATA-3 occupies genes in both Th1 and Th2 cells and, unexpectedly, shares a large proportion of targets with T-bet. Re-complementation of T-bet alters the expression of these genes in a manner that mirrors their differential expression between Th1 and Th2 lineages. These data show that the choice between Th1 and Th2 lineage commitment is the result of the opposing action of T-bet and GATA-3 at a shared set of target genes and may provide a general paradigm for the interaction of lineage-specifying transcription factors.