Prediction of regulatory transcription factors in T helper cell differentiation and maintenance.

Yue-Hien Lee, Manuela Benary, Ria Baumgrass, Hanspeter Herzel
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Abstract

Naive T-helper (Th) cells differentiate into distinct lineages including Th1, Th2, Th17 and regulatory T (Treg) cells. Each of these Th-lineages has specific functions in immune defense and T cell homeostasis. Th cell fate decisions and commitment are dependent on the kind and strength of T cell stimulation and the subsequent gene expression profiles. Our analysis targeted the identification of new regulatory transcription factor binding sites (TFBSs) in the promoter regions of up- and down-regulated genes in Treg cell differentiation and lineage maintenance. For this approach we compared different gene groups from global gene expression studies with background models of randomly selected genes to identify significantly overrepresented TFBSs. Results of our analysis suggest that Ets and IRF family members contribute to the regulation of the initial induction of Treg cells. Furthermore, we identified the overrepresented TFBS-pairs Runx-NFAT and GATA3-Foxp3 in Treg specific genes and Foxp3 dependent genes, respectively. Interestingly, previous studies have observed functional interactions of both TFBS-pairs in T cells. This study provides a starting point for further investigations to elucidate the transcriptional network in Treg cells.

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调控转录因子在辅助T细胞分化和维持中的预测。
幼稚T辅助细胞(Th)分化为不同的谱系,包括Th1、Th2、Th17和调节性T (Treg)细胞。每一种th谱系在免疫防御和T细胞稳态中都有特定的功能。细胞命运的决定和承诺取决于T细胞刺激的种类和强度以及随后的基因表达谱。我们的分析目标是在Treg细胞分化和谱系维持中上调和下调基因的启动子区域发现新的调控转录因子结合位点(TFBSs)。对于这种方法,我们将来自全球基因表达研究的不同基因组与随机选择的基因背景模型进行比较,以确定显著过度代表的TFBSs。我们的分析结果表明,Ets和IRF家族成员参与了Treg细胞的初始诱导调控。此外,我们在Treg特异性基因和Foxp3依赖基因中分别鉴定了过量代表的tfbs对Runx-NFAT和GATA3-Foxp3。有趣的是,之前的研究已经观察到这两种tfbs对在T细胞中的功能相互作用。本研究为进一步研究Treg细胞的转录网络提供了一个起点。
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