title: An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chung-Wei
authors.initials: CW
authors.lastname: Yang
authors.affiliation: Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ho-Chen
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Departments of Pediatrics and Clinical Laboratory, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.affiliation: Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Li-Kai
authors.initials: LK
authors.lastname: Tsai
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D030541:Databases, Genetic; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D006801:Humans; D008159:Lumbar Vertebrae / Q000473:pathology; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics