CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
CRDA, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.
Ther Adv Respir Dis. 2021 Jan-Dec;15:1753466621995045. doi: 10.1177/1753466621995045.
Idiopathic pulmonary fibrosis (IPF) is a rare form of immune-mediated interstitial lung disease characterized by progressive pulmonary fibrosis and scarring. The pathogenesis of IPF is still unclear. Gene fusion events exist universally during transcription and show alternated patterns in a variety of lung diseases. Therefore, the comprehension of the function of gene fusion in IPF might shed light on IPF pathogenesis research and facilitate treatment development.
In this study, we included 91 transcriptome datasets from the National Center for Biotechnology Information (NCBI), including 52 IPF patients and 39 healthy controls. We detected fusion events in these datasets and probed gene fusion-associated differential gene expression and functional pathways. To obtain robust results, we corrected the batch bias across different projects.
We identified 1550 gene fusion events in all transcriptomes and studied the possible impacts of IL7 = AC083837.1 gene fusion. The two genes locate adjacently in chromosome 8 and share the same promoters. Their fusion is associated with differential expression of 282 genes enriched in six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 35 functional gene sets. Gene ontology (GO) enrichment analysis shows that IL7 = AC083837.1 gene fusion is associated with the enrichment of 187 gene sets. The co-expression network of interleukin-7 (IL7) indicates that decreased IL7 expression is associated with many pathways that regulate IPF progress.
Based on the results, we conclude that IL7 = AC083837.1 gene fusion might exacerbate fibrosis in IPF enhancing activities of natural killer cell-mediated cytotoxicity, skin cell apoptosis, and vessel angiogenesis, the interaction of which contributes to the development of fibrosis and the deterioration of respiratory function of IPF patients. Our work unveils the possible roles of gene fusion in regulating IPF and demonstrates that gene fusion investigation is a valid approach in probing immunologic mechanisms and searching potential therapeutic targets for treating IPF.
特发性肺纤维化（IPF）是一种罕见的免疫介导性间质性肺病，其特征为进行性肺纤维化和瘢痕形成。IPF 的发病机制尚不清楚。基因融合事件在转录过程中普遍存在，并在多种肺部疾病中呈现交替模式。因此，了解基因融合在 IPF 中的功能可能有助于研究 IPF 的发病机制，并促进治疗方法的开发。
本研究纳入了来自美国国立生物技术信息中心（NCBI）的 91 个转录组数据集，包括 52 名 IPF 患者和 39 名健康对照者。我们在这些数据集中检测了融合事件，并探究了基因融合相关的差异基因表达和功能途径。为了获得稳健的结果，我们纠正了不同项目之间的批次偏差。
我们在所有转录组中鉴定了 1550 个基因融合事件，并研究了 IL7=AC083837.1 基因融合的可能影响。这两个基因位于 8 号染色体上相邻位置，具有相同的启动子。它们的融合与 282 个基因的差异表达相关，这些基因富集于六个京都基因与基因组百科全书（KEGG）途径和 35 个功能基因集。基因本体（GO）富集分析表明，IL7=AC083837.1 基因融合与 187 个基因集的富集相关。白细胞介素-7（IL7）的共表达网络表明，IL7 表达降低与许多调节 IPF 进展的通路相关。
基于这些结果，我们得出结论，IL7=AC083837.1 基因融合可能通过增强自然杀伤细胞介导的细胞毒性、皮肤细胞凋亡和血管生成，加重 IPF 中的纤维化，这些通路的相互作用导致纤维化的发展和 IPF 患者呼吸功能的恶化。我们的工作揭示了基因融合在调节 IPF 中的可能作用，并表明基因融合研究是探究免疫机制和寻找治疗 IPF 的潜在治疗靶点的有效方法。
