Transcriptomic insights into epigenetic and immunomodulatory roles of nuclear histone genes in bladder cancer: A bioinformatics approach.

Bladder cancer (BC) poses a significant global health and economic burden due to its high recurrence rates, progression risks, and the need for lifelong surveillance. Despite advances in diagnosis and treatment, reliable molecular biomarkers for prognosis and therapeutic targeting remain limited. In this study, we used an integrative bioinformatics approach to identify key dysregulated nuclear genes in BC, focusing on histone variants because of their essential role in chromatin organization and gene regulation. Using RNA-seq data, we performed a quality assessment, aligned reads with STAR, and conducted differential expression analysis using DESeq2. A unique gene expression pattern was seen between the cancer and control groups. From the DEGs, nuclear genes were curated using the NCBI Gene database and analysed their network topology via STRING and Cytoscape. MCODE found the complex cluster, and CytoHubba identified key hub genes, notably histone genes HIST1H3D (H3C4), HIST1H4E (H4C5), and HIST1H4B (H4C2). Functional enrichment via clusterProfiler highlighted roles in chromatin assembly, nucleosome organization, and centromeric dynamics. Notably, pathway analysis revealed links to systemic lupus erythematosus (SLE), neutrophil extracellular trap formation, and transcriptional misregulation, suggesting immunomodulatory roles. Kaplan-Meier survival analysis of patient cohorts using the KM-plotter tool revealed that higher expression of HIST1H4E and HIST1H4B was associated with improved survival outcomes. These findings emphasize the epigenetic and immunological roles of nuclear histone genes in BC progression and lay the groundwork for future translational research aimed at diagnostic and therapeutic advancements.