New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells.
New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells.
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DOI：
10.1371/journal.pone.0062849
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Santisteban P
中科院分区：
文献类型：
--
作者：
Fernández LP;López-Márquez A;Martínez AM;Gómez-López G;Santisteban P
FoxE1是一种甲状腺特异的叉头转录因子，对甲状腺发育以及成人甲状腺分化状态的维持至关重要。FoxE1识别并结合存在于甲状腺球蛋白(TG)和甲状腺过氧化物酶(TPO)启动子中的短DNA序列，但FoxE1与除TG和TPO启动子以外的其他调控区域的结合几乎仍未被探索。提高对FoxE1调节功能的了解对于阐明其在内分泌综合征和癌症易感性中的作用是必要的。为了进一步研究FoxE1下游靶点，我们在敲除FoxE1后进行了全基因组表达筛查，并对FoxE1在甲状腺滤泡细胞中的转录网络获得了新的见解。经验证，当FoxE1沉默时，Adamts9、CDH1、DUOX2和S100a4为上调基因，Casp4、Creld2、Dusp5、Etw5、Hsp5a、Nr4a2和Tm4sf1为下调基因。在FoxE1调控基因的启动子区域以及经典甲状腺基因Nis、Pax8和Titf1的启动子中，我们进行了与NF1/CTF结合序列非常接近的FoxE1结合基序的电子搜索，就像之前对其他叉头因子所描述的那样。通过染色质免疫沉淀，我们在体内检测到FoxE1与两个相关的甲状腺基因Nis和DUOX2的新调节区的特异性结合。此外，我们还证实了FoxE1和NF1/CTF同时与Nis上游增强子区结合，以及这两种转录因子对Nis启动子的明显功能激活。为了寻找在甲状腺细胞中潜在的FoxE1功能下游介质，我们鉴定了两个新的直接FoxE1靶基因。据我们所知，这是关于Nis和DUOX2在执行FoxE1触发的转录程序中的含义的第一个证据。此外，本研究还指出了FoxE1在甲状腺细胞大量基因调控中的重要作用。
FoxE1 is a thyroid-specific forkhead transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. FoxE1 recognizes and binds to a short DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, but FoxE1 binding to regulatory regions other than Tg and Tpo promoters remains almost unexplored. Improving knowledge of the regulatory functions of FoxE1 is necessary to clarify its role in endocrine syndromes and cancer susceptibility. In order to further investigate downstream FoxE1 targets, we performed a genome-wide expression screening after knocking-down FoxE1 and obtained new insights into FoxE1 transcriptional networks in thyroid follicular cells. After validation, we confirmed Adamts9, Cdh1, Duox2 and S100a4 as upregulated genes and Casp4, Creld2, Dusp5, Etv5, Hsp5a, Nr4a2 and Tm4sf1 as downregulated genes when FoxE1 was silenced. In promoter regions of putative FoxE1-regulated genes and also in the promoters of the classical thyroid genes Nis, Pax8 and Titf1, we performed an in silico search of the FoxE1 binding motif that was in close proximity to the NF1/CTF binding sequence, as previously described for other forkhead factors. Using chromatin immunoprecipitation we detected specific in vivo FoxE1 binding to novel regulatory regions in two relevant thyroid genes, Nis and Duox2. Moreover, we demonstrated simultaneous binding of FoxE1 and NF1/CTF to the Nis upstream enhancer region, as well as a clear functional activation of the Nis promoter by both transcription factors. In search for potential downstream mediators of FoxE1 function in thyroid cells, we identified two novel direct FoxE1 target genes. To our knowledge, this is the first evidence regarding the implication of Nis and Duox2 in executing the transcriptional program triggered by FoxE1. Furthermore, this study points out the important role of FoxE1 in the regulation of a large number of genes in thyroid cells.
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DOI：
10.1158/1055-9965.epi-08-0630
发表时间：
2008-12
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
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通讯作者：
Goggins M
影响因子：
14.9
作者：
Al-Shahrour F;Minguez P;Tárraga J;Medina I;Alloza E;Montaner D;Dopazo J
通讯作者：
Dopazo J
影响因子：
30.8
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通讯作者：
Stefansson, Kari
影响因子：
4.8
作者：
De la Vieja, Antonio;Reed, Mia D.;Carrasco, Nancy
通讯作者：
Carrasco, Nancy
影响因子：
30.8
作者：
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通讯作者：
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