FN1, Collagen, MMP-2, and Lumican Associated with ECM Organization with Multiple Signaling Pathways Dysfunction in Schizophrenia Pathogenesis by Network Biology Approaches

Abstract

Schizophrenia (SZ) is a chronic and devastating mental illness that affects around 20 million individuals worldwide. Cognitive deficits and structural and functional changes of the brain, abnormalities of brain ECM components, chronic neuroinflammation, and devastating clinical manifestation during SZ are likely etiological factors shown by affected individuals. However, the pathophysiological events associated with multiple regulatory pathways involved in the brain of this complex disorder are still unclear. This study aimed to develop a pipeline based on bioinformatics and machine learning approaches for identifying potential therapeutic targets involving possible biological mechanisms from SZ patients and healthy volunteers. 420 overlapping DEGs from three RNA-seq datasets were identified. GO, and pathways analysis showed several biological mechanisms enriched by the commonly shared DEGs, including ECM organization, collagen fibril organization, integrin signaling pathway, inflammation mediated by chemokines and cytokines signaling pathway, and GABA-B receptor II and IL4 mediated signaling. 15 hub genes (FN1, COL1A1, COL3A1, COL1A2, COL5A1, COL2A1, COL6A2, COL6A3, MMP2, THBS1, DCN, LUM, HLA-A, HLA-C, and FBN1) were discovered by comprehensive analysis, which was mainly involved in the ECM organization and inflammatory signaling pathway. Furthermore, the miRNA target of the hub genes was analyzed with the random-forest-based approach software miRTarBase. In addition, the transcriptional factors and protein kinases regulating overlapping DEGs in SZ, namely, SUZ12, EZH2, TRIM28, TP53, EGR1, CSNK2A1, GSK3B, CDK1, and MAPK14, were also identified. The results point to a new understanding that the hub genes (fibronectin 1, collagen, matrix metalloproteinase-2, and lumican) in the ECM organization and inflammatory signaling pathways may be involved in the SZ occurrence and pathogenesis.