Expression of human frataxin is regulated by transcription factors SRF and TFAP2.
Expression of human frataxin is regulated by transcription factors SRF and TFAP2.
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DOI：
10.1371/journal.pone.0012286
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发表时间：
2010-08-20
期刊：
影响因子：
3.7
通讯作者：
Rouault TA
中科院分区：
文献类型：
--
作者：
Li K;Singh A;Crooks DR;Dai X;Cong Z;Pan L;Ha D;Rouault TA
Friedreich共济失调是一种常染色体隐性遗传性神经退行性疾病，是由于Frataxin基因(FXN)第一内含子中三重核苷酸GAA重复序列扩增导致FXN表达水平降低所致。在受影响的Friedreich共济失调患者组织中提高Frataxin的表达水平可能会显著减缓疾病的进展。我们利用生物信息学工具结合染色质免疫沉淀和电泳迁移率改变分析来确定影响FXN基因转录的转录因子。我们发现转录因子SRF和TFAP2直接与FXN启动子序列结合。FXN启动子中的SRF和TFAP2结合序列增强了荧光素酶结构的转录，而预测的SRF或TFAP2结合位点的突变显著降低了FXN启动子的活性。进一步的分析表明，SRF和TFAP2介导的转录活性依赖于位于第一个FXN外显子下游的调控元件。最后，SRF或TFAP2的过表达显著增加了HEK293细胞中Frataxin的mRNA和蛋白水平，在SH-SY5Y细胞和携带SRF或TFAP2的Friedreich共济失调患者淋巴母细胞中，Frataxin的mRNA水平也显著升高。我们鉴定了两个转录因子，SRF和TFAP2，以及一个包含类似EGR3序列的内含子元件，它们共同调节FXN基因的表达。通过对影响Frataxin表达的分子因素提供新的机制见解，我们的结果应该有助于发现治疗Friedreich共济失调的新治疗靶点。
Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression. We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2. We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia.
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DOI：
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发表时间：
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DOI：
10.1016/s0925-4439(01)00041-2
发表时间：
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