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Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the  SMN1  gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes ( Bmp4 ,  Serpine1 ,  Gata6 ,  Ptgs2 ,  Bcl2 ,  IL6  and  Cntn1 ) of SMA were revealed, and are all known in the regulation of  TNFα  for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice,  TNFα  was up-regulated with attenuation of  Bmp4  and increase of  Serpine1  and  Gata6  (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of  Ptgs2  and  Bcl2  (a pathway in skeletal development) as well as  IL6  and  Cntn1  (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy.

An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy