Protective mechanism of TCF7L1 against retinal photoreceptor cell injury following retinitis pigmentosa based on the GEO database

• Published in: The FASEB journal 2023-05, Vol.37 (5), p.e22885-n/a
• Main Authors: Yin, Yuan, Wu, Shuai, Niu, Lingzhi, Huang, Shiwei
• Format: Article
• Language: English
• Subjects: bioinformatics analysis; cell apoptosis; Databases, Genetic; gene expression omnibus database; Gene Expression Profiling - methods; Gene Regulatory Networks; Humans; Microarray Analysis; photoreceptor cell injury; Photoreceptor Cells, Vertebrate; retinitis pigmentosa; Retinitis Pigmentosa - genetics; transcription factor; Transcription Factor 7-Like 1 Protein; transcription factor 7‐like 1; Wnt signaling pathway
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202201737RR

Recent studies have reported the promising value of differential gene expression analysis and weighted gene coexpression network analysis (WGCNA) for identifying disease biomarkers. Based on this method, this study intends to characterize the hub genes and pathways related to retinal photoreceptor cell (PRC) injury in the context of retinitis pigmentosa (RP). A total of 53 coexpression modules were identified by WGCNA, among which lightpink4, darkolivegreen, tan4, blue2, skyblue2, and navajowhite2 ranked at the top. By analyzing the RP microarrays retrieved from the GEO database, 338 differentially expressed genes (DEGs) were identified in the RP samples. Forty‐five candidate genes were selected from these DEGs by intersection with the genes in the coexpression modules. These intersection genes were subjected to GO and KEGG analyses. Furthermore, the genes and pathways involved in PRC damage were identified based on analyses utilizing GeneCards and STRING tools. Transcription factor 7‐like 1 (TCF7L1, also called TCF3) was suggested to participate in the RP‐associated PRC damage through the Wnt signaling pathway. It was validated in a blue light‐irradiated cell model that TCF7L1 overexpression boosted PRC viability and repressed apoptosis. Inhibition of the Wnt signaling pathway also contributed to protective effects. Together, the data mentioned above supported the conclusion that either elevation of TCF7L1 or blockade of the Wnt signaling pathway could prevent RP progression by protecting PRCs from damage. Molecular mechanism by which TCF7L1 protects against retinal photoreceptor cell injury after retinitis pigmentosa. The Wnt signaling pathway was activated in the retinitis pigmentosa patients, while TCF7L1 was regulated by β‐catenin, and expression was inhibited. Furthermore, due to the accumulation of damage in PRCs, the expression of BAX, a positive regulator of apoptosis, was significantly upregulated. In contrast, the protein level of Bcl‐2, a negative regulator, was decreased, ultimately leading to a decrease in cell viability and promoting apoptosis. The addition of XAV939, an inhibitor of the β‐catenin signaling pathway, unblocked the inhibitory effect of β‐catenin on TCF7L1 expression and led to the downregulation of BAX and upregulation of Bcl‐2 expression, thus effectively preventing apoptosis and improving RP symptoms.