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<p>Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene, leading to progressive muscle degeneration. Due to the complexity and multifactorial nature of DMD pathogenesis, a systems biology approach was employed to identify key regulatory components by integrating transcription factors (TFs), microRNAs (miRNAs), and protein–protein interactions. A combinatorial, scale-free hierarchical network was constructed using 2,619 nodes and 69,588 edges derived from DisGeNET, literature curated genes, and experimentally validated miRNA and TFs interactions. Topological analysis identified 14 Bottleneck Hubs (Bn-Hs) based on high degree and betweenness centrality. Four functional modules were identified using MCODE plugin, which identifies densely connected regions (modules) in complex biological networks. Among the 14 identified Bn-Hs, five Bn-Hs (VEGFA, MYC, ACTB, HIF1A, and FN1) exhibiting high inter-modular connectivity, while VEGFA emerging as the most influential node, highlighting its potential as a key therapeutic target in DMD. Gene ontology analysis indicated enrichment in immune response, signaling, cell migration and extracellular matrix organization. Pathway enrichment analysis further linked genes such as IFNG, IL10, IL6, TNF, and TLR4 to other disorders like Chagas disease, cancer, and HIV, likely due to shared dysregulated pathways. Motif analysis identified two TFs (CREB1, BRD4) and four miRNAs (miR-107, miR-424-5p, miR-34a-5p, miR-29b-3p) commonly regulating the top five Bn-Hs through coherent feed-forward loop motifs. These findings suggest that targeting key Bn-Hs and their regulators (TFs and miRNAs) may guide therapeutic strategies, such as the development of miRNA-based interventions or small-molecule modulators for DMD treatment.</p>

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Identification of key regulators in Duchenne muscular dystrophy combinatorial network: a systems biology approach

  • 期刊论文

  • 发表日期：

    2025年11月4日

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  • Shashikala,
  • Vibha Rani,
  • Shazia Haider

摘要

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene, leading to progressive muscle degeneration. Due to the complexity and multifactorial nature of DMD pathogenesis, a systems biology approach was employed to identify key regulatory components by integrating transcription factors (TFs), microRNAs (miRNAs), and protein–protein interactions. A combinatorial, scale-free hierarchical network was constructed using 2,619 nodes and 69,588 edges derived from DisGeNET, literature curated genes, and experimentally validated miRNA and TFs interactions. Topological analysis identified 14 Bottleneck Hubs (Bn-Hs) based on high degree and betweenness centrality. Four functional modules were identified using MCODE plugin, which identifies densely connected regions (modules) in complex biological networks. Among the 14 identified Bn-Hs, five Bn-Hs (VEGFA, MYC, ACTB, HIF1A, and FN1) exhibiting high inter-modular connectivity, while VEGFA emerging as the most influential node, highlighting its potential as a key therapeutic target in DMD. Gene ontology analysis indicated enrichment in immune response, signaling, cell migration and extracellular matrix organization. Pathway enrichment analysis further linked genes such as IFNG, IL10, IL6, TNF, and TLR4 to other disorders like Chagas disease, cancer, and HIV, likely due to shared dysregulated pathways. Motif analysis identified two TFs (CREB1, BRD4) and four miRNAs (miR-107, miR-424-5p, miR-34a-5p, miR-29b-3p) commonly regulating the top five Bn-Hs through coherent feed-forward loop motifs. These findings suggest that targeting key Bn-Hs and their regulators (TFs and miRNAs) may guide therapeutic strategies, such as the development of miRNA-based interventions or small-molecule modulators for DMD treatment.