Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers.
Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers.
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DOI：
10.1242/dmm.030536
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发表时间：
2017-11-01
影响因子：
4.3
通讯作者：
Napierala M
中科院分区：
文献类型：
--
作者：
Napierala JS;Li Y;Lu Y;Lin K;Hauser LA;Lynch DR;Napierala M
弗里德赖希共济失调症（FRDA）是一种常染色体隐性神经退行性疾病，通常由frataxin （FXN）基因内含子1 GAA重复序列的大量纯合扩增引起。与杂合子携带者或健康对照相比，GAA扩增纯合子的FRDA患者FXN mRNA和蛋白水平较低。Frataxin是一种参与铁硫簇合成的线粒体蛋白，许多FRDA表型是由于FXN表达降低导致细胞代谢缺陷造成的。目前，尚无针对FRDA的有效治疗方法，缺乏衡量治疗试验结果和/或衡量疾病进展的生物标志物。周围组织，包括血细胞、颊细胞和皮肤成纤维细胞，可以很容易地从FRDA患者中分离出来，并用于确定疾病发病机制的分子标志。例如，FXN mRNA和蛋白质水平以及FXN gaa -重复束长度通常使用所有这些细胞类型来确定。然而，由于这些组织不直接参与疾病的发病机制，它们作为疾病分子方面模型的相关性尚未确定。在此，我们进行了无偏倚的RNA测序，以分析来自18名FRDA患者和17名未受影响的对照个体的成纤维细胞系的转录组。生物信息学分析显示，FRDA成纤维细胞中编码质膜溶质载体蛋白的基因表达显著上调。相反，编码辅助因子和参与细胞质和线粒体蛋白质合成的酶的基因表达在FRDA成纤维细胞中持续下降。最后，将FRDA成纤维细胞中差异表达的基因与先前发表的FRDA血细胞中定义的三个基因表达特征进行比较，发现独立数据集之间存在大量重叠，包括相应的抗氧化防御基因表达不足。总之，这些结果表明，来自外周组织的细胞的基因表达谱实际上可以一致地揭示疾病的新分子途径。当在统计上有意义的样本组大小上进行时，利用外周组织进行无偏倚的全局分析对于FRDA疾病生物标志物的发现和验证至关重要。摘要：通过RNA测序对弗里德赖希共济失调成纤维细胞的转录组分析表明，这种外周组织可以作为发现基因表达生物标志物的疾病模型。
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron–sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN. Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking. Peripheral tissues, including blood cells, buccal cells and skin fibroblasts, can readily be isolated from FRDA patients and used to define molecular hallmarks of disease pathogenesis. For instance, FXN mRNA and protein levels as well as FXN GAA-repeat tract lengths are routinely determined using all of these cell types. However, because these tissues are not directly involved in disease pathogenesis, their relevance as models of the molecular aspects of the disease is yet to be decided. Herein, we conducted unbiased RNA sequencing to profile the transcriptomes of fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Bioinformatic analyses revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins in FRDA fibroblasts. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in FRDA fibroblasts. Finally, comparison of genes differentially expressed in FRDA fibroblasts to three previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease. When performed on statistically meaningful sample group sizes, unbiased global profiling analyses utilizing peripheral tissues are critical for the discovery and validation of FRDA disease biomarkers. Summary: Transcriptome profiling of Friedreich's ataxia fibroblasts by RNA sequencing reveals that this peripheral tissue can be used as a disease model for gene expression biomarker discovery.
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影响因子：
3.8
作者：
Deutsch, Eric C.;Santani, Avni B.;Perlman, Susan L.;Farmer, Jennifer M.;Stolle, Catherine A.;Marusich, Michael F.;Lynch, David R.
通讯作者：
Lynch, David R.
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影响因子：
3.5
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Koeppen, Arnulf H.;Ramirez, R. Liane;Yu, Devin;Collins, Sarah E.;Qian, Jiang;Parsons, Patrick J.;Yang, Karl X.;Chen, Zewu;Mazurkiewicz, Joseph E.;Feustel, Paul J.
通讯作者：
Feustel, Paul J.
影响因子：
3.5
作者：
Chantrel-Groussard, K;Geromel, V;Rustin, P
通讯作者：
Rustin, P
影响因子：
11.2
作者：
Coppola, Giovanni;Burnett, Ryan;Perlman, Susan;Versano, Revital;Gao, Fuying;Plasterer, Heather;Rai, Myriam;Sacca, Francesco;Filla, Alessandro;Lynch, David R.;Rusche, James R.;Gottesfeld, Joel M.;Pandolfo, Massimo;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
影响因子：
3.7
作者：
Hayashi G;Cortopassi G
通讯作者：
Cortopassi G