Identification of key genes and signaling pathway in the pathogenesis of Huntington's disease via bioinformatics and next generation sequencing data analysis

Huntingtons disease (HD) is the primary cause of progressive motor deficits, psychiatric symptoms, and cognitive impairment. The exact molecular mechanisms of HD pathogenesis are largely unknown. This investigation aims to identify the hub genes, miRNA and TFs in HD and explore their potential molecular regulatory network. Next generation sequencing (NGS) dataset (GSE105041) was extracted from the Gene Expression Omnibus (GEO) database. An integrated bioinformatics pipeline including identification of differentially expressed genes (DEGs), Gene ontology and REACTOME pathway enrichment analysis, protein-protein interaction (PPI) network and module analysis, miRNA-hub gene regulatory network analysis and TF-hub gene regulatory network analysis, and receiver operating characteristic curve (ROC) analysis were applied to identify hub genes, miRNA and TFs, and key drivers of HD pathogenesis. We identified 958 DEGs in the discovery phase, consisting of 479 up regulated genes and 479 down regulated genes. GO and REACTOME enrichment analyses of the 479 up regulated genes and 479 down regulated genes showed that they were mainly involved in multicellular organismal process, developmental process, signaling by GPCR and MHC class II antigen presentation. Further analysis of the PPI network using Cytoscape and PEWCC plugins identified 10 hub genes, including LRRK2, MTUS2, HOXA1, IL7R, ERBB3, EGFR, TEX101, WDR76, NEDD4L and COMT. Possible target miRNAs and TFs, including hsa-mir-1292-5p, hsa-mir-4521, ESRRB and SREBF1, were predicted by constructing a miRNA-hub gene regulatory network analysis and TF-hub gene regulatory network. This investigation used bioinformatics methods to explore the molecular pathogenesis of HD, and identified potential molecular markers. These molecular markers might provide novel ideas and methods for the early diagnosis, treatment, and monitoring of HD.