Xue Ruoyan, Tang Qi, Zhang Yongli, Xie Mengyao, Li Chen, Wang Shu, Yang Hua
Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Genet. 2022 Feb 22;13:799783. doi: 10.3389/fgene.2022.799783. eCollection 2022.
Loss or partial loss of one X chromosome induces Turner syndrome (TS) in females, causing major medical concerns, including otologic disorders. However, the underlying genetic pathophysiology of otologic disorders in TS is mostly unclear. Ear-related genes of TS (TSEs) were identified by analyzing differentially expressed genes (DEGs) in two Gene Expression Omnibus (GEO)-derived expression profiles and ear-genes in the Comparative Toxicogenomic Database (CTD). Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) analyses; Gene Set Enrichment Analysis (GSEA); and Gene Set Variation Analysis (GSVA) were adopted to study biological functions. Moreover, hub genes within the TSEs were identified by assessing protein-protein interaction (PPI), gene-microRNA, and gene-transcription factor (TF) networks. Drug-Gene Interaction Database (DGIdb) analysis was performed to predict molecular drugs for TS. Furthermore, three machine-learning analysis outcomes were comprehensively compared to explore optimal biomarkers of otologic disorders in TS. Finally, immune cell infiltration was analyzed. The TSEs included 30 significantly upregulated genes and 14 significantly downregulated genes. Enrichment analyses suggested that TSEs play crucial roles in inflammatory responses, phospholipid and glycerolipid metabolism, transcriptional processes, and epigenetic processes, such as histone acetylation, and their importance for inner ear development. Subsequently, we described three hub genes in the PPI network and confirmed their involvement in Wnt/β-catenin signaling pathway and immune cell regulation and roles in maintaining normal auditory function. We also constructed gene-microRNA and gene-TF networks. A novel biomarker (SLC25A6) of the pathogenesis of otologic disorders in TS was identified by comprehensive comparisons of three machine-learning analyses with the best predictive performance. Potential therapeutic agents in TS were predicted using the DGIdb. Immune cell infiltration analysis showed that TSEs are related to immune-infiltrating cells. Overall, our findings have deepened the understanding of the pathophysiology of otologic disorders in TS and made contributions to present a promising biomarker and treatment targets for in-depth research.
一条X染色体的缺失或部分缺失会导致女性患特纳综合征（TS），引发包括耳科疾病在内的重大医学问题。然而，TS中耳科疾病的潜在遗传病理生理学大多尚不清楚。通过分析两个来自基因表达综合数据库（GEO）的表达谱中的差异表达基因（DEG）以及比较毒理基因组学数据库（CTD）中的耳相关基因，确定了TS的耳相关基因（TSE）。随后，采用基因本体论（GO）、京都基因与基因组百科全书（KEGG）和疾病本体论（DO）分析；基因集富集分析（GSEA）；以及基因集变异分析（GSVA）来研究生物学功能。此外，通过评估蛋白质-蛋白质相互作用（PPI）、基因-微小RNA和基因-转录因子（TF）网络，确定了TSE中的核心基因。进行药物-基因相互作用数据库（DGIdb）分析以预测TS的分子药物。此外，综合比较三种机器学习分析结果，以探索TS中耳科疾病的最佳生物标志物。最后，分析了免疫细胞浸润情况。TSE包括30个显著上调的基因和14个显著下调的基因。富集分析表明，TSE在炎症反应、磷脂和甘油酯代谢、转录过程以及表观遗传过程（如组蛋白乙酰化）中起关键作用，及其对内耳发育的重要性。随后，我们描述了PPI网络中的三个核心基因，并证实它们参与Wnt/β-连环蛋白信号通路和免疫细胞调节以及在维持正常听觉功能中的作用。我们还构建了基因-微小RNA和基因-TF网络。通过对三种具有最佳预测性能的机器学习分析进行综合比较，确定了TS中耳科疾病发病机制的一种新型生物标志物（SLC25A6）。使用DGIdb预测了TS中的潜在治疗药物。免疫细胞浸润分析表明，TSE与免疫浸润细胞有关。总体而言，我们的研究结果加深了对TS中耳科疾病病理生理学的理解，并为深入研究提供了一个有前景的生物标志物和治疗靶点做出了贡献。
