Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia.
Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia.
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DOI：
10.1093/nar/gkn604
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发表时间：
2008-11
影响因子：
14.9
通讯作者：
Napierala M
中科院分区：
文献类型：
--
作者：
Soragni E;Herman D;Dent SY;Gottesfeld JM;Wells RD;Napierala M
Friedreich共济失调(Friedreich ataxia，FRDA)是由于FXN基因第一内含子中GAA·TTC重复序列过度膨胀，抑制转录，导致Frataxin缺失所致。FXN基因是一个很好的治疗干预目标，因为(I)98%的患者携带相同类型的突变，(Ii)突变是内含子的，因此Fxn编码序列不受影响，(Iii)∼减少50%的Frataxin杂合子GAA·TTC扩展携带者没有症状。由于缺乏合适的FRDA分子模型，FRDA治疗策略的发现受到阻碍。在这里，我们介绍了通过在GFP报告基因的内含子中插入560个GAA·TTC重复序列来开发一种新的细胞系作为FRDA的分子模型。GFP_(GaA·TTC)560微型基因概括了突变的FXN基因的分子特征，即报告基因转录抑制、报告蛋白水平降低以及重复序列附近组蛋白的低乙酰化和高甲基化。此外，选定的组蛋白脱乙酰酶抑制剂可以刺激FXN基因的表达，增加GFP_(GAA·TTC)560报告基因的表达。这种FRDA模型可以适应高通量分析，以寻找治疗这种疾病的新疗法。
Friedreich ataxia (FRDA) is caused by hyperexpansion of GAA•TTC repeats located in the first intron of the FXN gene, which inhibits transcription leading to the deficiency of frataxin. The FXN gene is an excellent target for therapeutic intervention since (i) 98% of patients carry the same type of mutation, (ii) the mutation is intronic, thus leaving the FXN coding sequence unaffected and (iii) heterozygous GAA•TTC expansion carriers with ∼50% decrease of the frataxin are asymptomatic. The discovery of therapeutic strategies for FRDA is hampered by a lack of appropriate molecular models of the disease. Herein, we present the development of a new cell line as a molecular model of FRDA by inserting 560 GAA•TTC repeats into an intron of a GFP reporter minigene. The GFP_(GAA•TTC)560 minigene recapitulates the molecular hallmarks of the mutated FXN gene, i.e. inhibition of transcription of the reporter gene, decreased levels of the reporter protein and hypoacetylation and hypermethylation of histones in the vicinity of the repeats. Additionally, selected histone deacetylase inhibitors, known to stimulate the FXN gene expression, increase the expression of the GFP_(GAA•TTC)560 reporter. This FRDA model can be adapted to high-throughput analyses in a search for new therapeutics for the disease.
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影响因子：
14.9
作者：
Greene E;Mahishi L;Entezam A;Kumari D;Usdin K
通讯作者：
Usdin K
影响因子：
14.9
作者：
Bacolla A;Collins JR;Gold B;Chuzhanova N;Yi M;Stephens RM;Stefanov S;Olsh A;Jakupciak JP;Dean M;Lempicki RA;Cooper DN;Wells RD
通讯作者：
Wells RD
DOI：
10.1073/pnas.94.14.7452
发表时间：
1997-07-08
影响因子：
11.1
作者：
Cossee, M;Schmitt, M;Koenig, M
通讯作者：
Koenig, M
影响因子：
9.8
作者：
Bidichandani, SI;Ashizawa, T;Patel, PI
通讯作者：
Patel, PI
影响因子：
14.9
作者：
Bowater, RP;Jaworski, A;Wells, RD
通讯作者：
Wells, RD