Transcriptomic meta-analysis reveals ERRα-mediated oxidative phosphorylation is downregulated in Fuchs' endothelial corneal dystrophy.
Transcriptomic meta-analysis reveals ERRα-mediated oxidative phosphorylation is downregulated in Fuchs' endothelial corneal dystrophy.
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DOI：
10.1371/journal.pone.0295542
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
迟发性Fuchs角膜内皮营养不良（FECD）是一种角膜退行性疾病，是角膜移植的主要适应症。在遗传学上，FECD患者可以被分类为在转录因子4基因中具有（RE+）或不具有（RE-）CTG三核苷酸重复扩增。FECD潜在的分子机制仍不清楚，虽然有合理的致病模型提出RE+ FECD。在这项研究中，我们对FECD角膜内皮的RNA测序数据集进行了荟萃分析，包括3个RE+数据集和2个RE-数据集，旨在比较RE+和RE- FECD的转录组学谱。进行基因差异表达分析、共表达网络分析和通路分析。RE+和RE-转录组之间存在着惊人的相似性。在RE+和RE-病例中，有1，184个基因显著上调，1，018个基因显著下调。通路分析确定了多个生物学过程，线粒体功能，能量相关过程，ER-核信号通路，去甲基化和RNA剪接显著富集，而小GT3介导的信号传导，肌动蛋白丝过程，细胞外基质组织，干细胞分化和中性粒细胞介导的免疫是积极的富集。翻译起始过程在RE+转录组中下调。基因共表达分析鉴定了具有相对不同的生物学过程的模块，所述生物学过程包括线粒体呼吸链复合物组装的下调。在RE+和RE-病例中，大多数氧化磷酸化（OXPHOS）亚基基因及其上游调控基因雌激素相关受体α（ESRRA）表达下调，ESRRA表达水平与OXPHOS亚基基因表达水平相关。荟萃分析提高了检测差异表达基因的能力。将差异表达分析与共表达分析相结合有助于理解潜在的分子机制。FECD RE+和RE-转录组特征与ERRα介导的OXPHOS相关途径中基因下调的标志非常相似。
Late-onset Fuchs’ endothelial corneal dystrophy (FECD) is a degenerative disease of cornea and the leading indication for corneal transplantation. Genetically, FECD patients can be categorized as with (RE+) or without (RE-) the CTG trinucleotide repeat expansion in the transcription factor 4 gene. The molecular mechanisms underlying FECD remain unclear, though there are plausible pathogenic models proposed for RE+ FECD. In this study, we performed a meta-analysis on RNA sequencing datasets of FECD corneal endothelium including 3 RE+ datasets and 2 RE- datasets, aiming to compare the transcriptomic profiles of RE+ and RE- FECD. Gene differential expression analysis, co-expression networks analysis, and pathway analysis were conducted. There was a striking similarity between RE+ and RE- transcriptomes. There were 1,184 genes significantly upregulated and 1,018 genes significantly downregulated in both RE+ and RE- cases. Pathway analysis identified multiple biological processes significantly enriched in both—mitochondrial functions, energy-related processes, ER-nucleus signaling pathway, demethylation, and RNA splicing were negatively enriched, whereas small GTPase mediated signaling, actin-filament processes, extracellular matrix organization, stem cell differentiation, and neutrophil mediated immunity were positively enriched. The translational initiation process was downregulated in the RE+ transcriptomes. Gene co-expression analysis identified modules with relatively distinct biological processes enriched including downregulation of mitochondrial respiratory chain complex assembly. The majority of oxidative phosphorylation (OXPHOS) subunit genes, as well as their upstream regulator gene estrogen-related receptor alpha (ESRRA), encoding ERRα, were downregulated in both RE+ and RE- cases, and the expression level of ESRRA was correlated with that of OXPHOS subunit genes. Meta-analysis increased the power of detecting differentially expressed genes. Integrating differential expression analysis with co-expression analysis helped understand the underlying molecular mechanisms. FECD RE+ and RE- transcriptomic profiles are much alike with the hallmark of downregulation of genes in pathways related to ERRα-mediated OXPHOS.
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影响因子：
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作者：
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