Phylogenetic and Functional Analysis Identifies Ets-1 as a Novel Regulator of the Th2 Cytokine Gene Locus
Phylogenetic and Functional Analysis Identifies Ets-1 as a Novel Regulator of the Th2 Cytokine Gene Locus
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DOI：
10.4049/jimmunol.0804162
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发表时间：
2010-02-01
影响因子：
4.4
通讯作者：
Vercelli, Donata
中科院分区：
文献类型：
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作者：
Strempel, Jannine M.;Grenningloh, Roland;Vercelli, Donata
Th2细胞因子基因座已成为协调基因表达的显着例子，其调节似乎植根于广泛的顺式调节区域。使用一种假设生成计算方法，将多物种（n = 11）序列比较与基于算法的转录因子结合位点预测相结合，我们试图识别进化上保守的非编码区（ECR）和它们之间共享的基序，这可能是共同调控的基础。预计 22 个转录因子家族在至少两个 Th2 ECR 中具有结合位点。这些共享基序根据其分布和相对频率进行的排名表明了转录因子家族之间的调控层次结构。 GATA 位点最为普遍且分布广泛，这与 GATA3 作为 Th2 主开关的已知作用一致。出乎意料的是，在几个 Th2 ECR 中也预测了 ETS 结构域蛋白的位点，并且发现这些位点中的大多数支持 Ets-1 的体外和体内结合。值得注意的是，在 Ets-1 缺陷小鼠产生的 Th2 细胞中，所有三种 Th2 细胞因子（IL-5、43 和 -4）的表达均显着且选择性降低。总的来说，这些数据表明 Ets-1 通过与整个 Th2 基因座的多个顺式调控区域相互作用，有助于 Th2 细胞因子基因调控。免疫学杂志，2010，184：1309-1316。
The Th2 cytokine gene locus has emerged as a remarkable example of coordinated gene expression, the regulation of which seems to be rooted in an extensive array of cis-regulatory regions. Using a hypothesis-generating computational approach that integrated multispecies (n = 11) sequence comparisons with algorithm-based transcription factor binding-site predictions, we sought to identify evolutionarily conserved noncoding regions (ECRs) and motifs shared among them, which may underlie coregulation. Twenty-two transcription factor families were predicted to have binding sites in at least two Th2 ECRs. The ranking of these shared motifs according to their distribution and relative frequency pointed to a regulatory hierarchy among the transcription factor families. GATA sites were the most prevalent and widely distributed, consistent with the known role of GATA3 as a Th2 master switch. Unexpectedly, sites for ETS-domain proteins were also predicted within several Th2 ECRs and the majority of these sites were found to support Ets-1 binding in vitro and in vivo. Of note, the expression of all three Th2 cytokines (IL-5, 43, and -4) was significantly and selectively decreased in Th2 cells generated from Ets-1-deficient mice. Collectively, these data suggest that Ets-1 contributes to Th2 cytokine gene regulation by interacting with multiple cis-regulatory regions throughout the Th2 locus. The Journal of Immunology, 2010, 184: 1309-1316.