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首页> 美国卫生研究院文献>Molecular Therapy. Nucleic Acids >Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE-SunTag
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Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE-SunTag

机译：白金TALE-VP64s或白金TALE-SunTag诱导弗里德赖奇共济失调细胞中的frataxin表达增加

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摘要

Frataxin gene (FXN) expression is reduced in Friedreich’s ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria’s iron metabolism. Platinum TALE (plTALE) proteins targeting the regulatory region of the FXN gene, fused with a transcriptional activator (TA) such as VP64 or P300, were used to increase the expression of that gene. Many effectors, plTALEVP64, plTALEp300, and plTALESunTag, targeting 14 sequences of the FXN gene promoter or intron 1 were produced. This permitted selection of 3 plTALEVP64s and 2 plTALESunTag that increased FXN gene expression by up to 19-fold in different Friedreich ataxia (FRDA) primary fibroblasts. Adeno-associated viruses were used to deliver the best effectors to the YG8R mouse model to validate their efficiencies in vivo. Our results showed that these selected plTALEVP64s or plTALESunTag induced transcriptional activity of the endogenous FXN gene as well as expression of the frataxin protein in YG8R mouse heart by 10-fold and in skeletal muscles by up to 35-fold. The aconitase activity was positively modulated by the frataxin level in mitochondria, and it was, thus, increased in vitro and in vivo by the increased frataxin expression.
机译：由于内含子1中GAA三核苷酸的数量增加，弗雷德赖奇共济失调患者的Frataxin基因（FXN）表达降低。该基因编码的Frataxin蛋白在线粒体的铁代谢中起重要作用。靶向FXN基因调节区的白金TALE（plTALE）蛋白与转录激活剂（TA）诸如VP64或P300融合在一起，用于增加该基因的表达。产生了靶向FXN基因启动子或内含子1的14个序列的许多效应子，plTALEVP64，plTALEp300和plTALESunTag。这允许选择3个plTALEVP64和2个plTALESunTag，它们在不同的Friedreich共济失调（FRDA）原代成纤维细胞中使FXN基因表达增加多达19倍。腺相关病毒被用来向YG8R小鼠模型提供最佳效应子，以验证其在体内的效率。我们的结果表明，这些选择的plTALEVP64s或plTALESunTag诱导内源性FXN基因的转录活性以及在YG8R小鼠心脏中的frataxin蛋白表达增加了10倍，在骨骼肌中表达了高达35倍。线粒体中frataxin的水平正调节着乌头酸的活性，因此frataxin的表达增加了体外和体内的乌头酸活性。

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