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Background <p>The global prevalence of myopia has risen sharply, particularly among children and adolescents in urban and highly educated populations. RNA modifications have been recognized as important regulators in myopia progression. However, the role of m<sup>5</sup>C, a crucial RNA modification, remains largely unexplored in myopia progression.</p> Methods <p>Key RNA modification-related genes were first identified through weighted gene co-expression network analysis (WGCNA), based on expression profiles of m<sup>6</sup>A‑, m<sup>1</sup>A‑, m<sup>5</sup>C‑, and m<sup>7</sup>G‑associated genes from the mouse myopic sclera dataset PRJCA000717. Pathway enrichment analysis was performed via Gene Set Enrichment Analysis (GSEA), and immune infiltration characteristics were evaluated using CIBERSORT. Further experimental validation included RT-qPCR and Western blotting to confirm <i>TET1</i> up-regulation in a hypoxia-induced model of human scleral fibroblasts (HSFs), and functional assessments via knockdown experiments.</p> Results <p>Utilizing WGCNA, we identified <i>Tet1</i>, an m<sup>5</sup>C demethylase, as a key gene associated with myopia. Its expression was significantly elevated in myopic scleral samples. We further confirmed the increased <i>TET1</i> expression in hypoxia-induced HSFs. <i>TET1</i> was found to be involved in pivotal biological processes and the scleral microenvironment. Immune cell infiltration analysis revealed a significant negative correlation between <i>Tet1</i> and eosinophils. GSEA indicated that <i>Tet1</i>‑related pathways include the proteasome, HIF‑1 signaling, and TGF‑β signaling. Knockdown of <i>TET1</i> reversed hypoxia‑induced increases in apoptosis, restored m<sup>5</sup>C modification levels, and promoted HSF proliferation. Additionally, <i>TET1</i> down‑regulation elevated COL1A1 protein expression while reducing α‑SMA, a key marker of scleral remodeling. Data from the GeneCards database showed that <i>Tet1</i> expression significantly correlated with several myopia‑related progression genes, including <i>Col2a1</i> (<i>p</i> = 0.002) and <i>Fbn1</i> (<i>p</i> &lt; 0.001).</p> Conclusion <p>Our study reveals substantial alterations in <i>TET1</i> expression and m<sup>5</sup>C modification in myopic sclera, providing new insights that may inform the development of novel diagnostic and therapeutic approaches for myopia management.</p>

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The m5C demethylase TET1 is identified as a key regulator of scleral remodeling in myopia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Shichong Jia,
  • Ludi Yang,
  • Pinghui Wei,
  • Jie Yu,
  • Guoge Han,
  • Yan Wang

摘要

Background

The global prevalence of myopia has risen sharply, particularly among children and adolescents in urban and highly educated populations. RNA modifications have been recognized as important regulators in myopia progression. However, the role of m5C, a crucial RNA modification, remains largely unexplored in myopia progression.

Methods

Key RNA modification-related genes were first identified through weighted gene co-expression network analysis (WGCNA), based on expression profiles of m6A‑, m1A‑, m5C‑, and m7G‑associated genes from the mouse myopic sclera dataset PRJCA000717. Pathway enrichment analysis was performed via Gene Set Enrichment Analysis (GSEA), and immune infiltration characteristics were evaluated using CIBERSORT. Further experimental validation included RT-qPCR and Western blotting to confirm TET1 up-regulation in a hypoxia-induced model of human scleral fibroblasts (HSFs), and functional assessments via knockdown experiments.

Results

Utilizing WGCNA, we identified Tet1, an m5C demethylase, as a key gene associated with myopia. Its expression was significantly elevated in myopic scleral samples. We further confirmed the increased TET1 expression in hypoxia-induced HSFs. TET1 was found to be involved in pivotal biological processes and the scleral microenvironment. Immune cell infiltration analysis revealed a significant negative correlation between Tet1 and eosinophils. GSEA indicated that Tet1‑related pathways include the proteasome, HIF‑1 signaling, and TGF‑β signaling. Knockdown of TET1 reversed hypoxia‑induced increases in apoptosis, restored m5C modification levels, and promoted HSF proliferation. Additionally, TET1 down‑regulation elevated COL1A1 protein expression while reducing α‑SMA, a key marker of scleral remodeling. Data from the GeneCards database showed that Tet1 expression significantly correlated with several myopia‑related progression genes, including Col2a1 (p = 0.002) and Fbn1 (p < 0.001).

Conclusion

Our study reveals substantial alterations in TET1 expression and m5C modification in myopic sclera, providing new insights that may inform the development of novel diagnostic and therapeutic approaches for myopia management.