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Background <p>Thymoma-associated myasthenia gravis (TAMG) represents the paraneoplastic subtype of MG and is characterized by autoantibodies against skeletal muscle proteins, such as acetylcholine receptor (AChR), titin, and ryanodine receptor (RyR). Thymic epithelial cells of TAMG patients overexpress neuronal and neuromuscular genes that code for MG autoantigen epitopes. This may contribute to the autoimmune breakdown in TAMG patients. This study explored whether such aberrant expression of autoimmune epitopes is regulated by their promoter CpG methylation profiles.</p> Methods <p>The thymoma bulk RNA sequencing, single cell RNA sequencing, and DNA methylation data were collected from 40 TAMG and 96 non-MG thymoma patients using three independent cohorts. A novel algorithm using a multiple linear regression model was developed to examine the gene promoter CpG island methylation status in TAMG and non-thymoma MG patients. The correlation between promoter CpG island and RNA expression in the TAMG thymoma was explored.</p> Results <p>In both TAMG and non-MG thymoma, the global promoter CpG islands were hypomethylated and were negatively correlated with RNA expression. The CpG islands at promoters of muscle-like epitope genes, <i>NEFM</i> and <i>RYR3</i>, were significantly hypomethylated in TAMG thymoma and negatively correlated with mRNA expression in both a primary and a verification cohort. For MG antigen genes <i>CHRNA1, TTN</i> and <i>RyR1</i>, the CHRNA1 promoter CpG site methylation correlated negatively with CHRNA1 RNA expression. However, there was no difference in promoter methylation status between TAMG and non-MG thymomas. For the <i>AIRE</i> gene, the promoter CPG islands were significantly hypermethylated and negatively correlated with mRNA expression. Both bulk and single cell RNA sequencing showed that key genes involved in the DNA CpG methylation pathways, including <i>DNMT1, UHRF1</i> and <i>HDAC1</i>, had a reduced expression in thymic epithelial cells of TAMG thymoma.</p> Conclusions <p>Our results indicate that the aberrant overexpression of muscle-like epitopes in TAMG might be driven by CpG island hypomethylation. This represents a novel mechanism for intrathymic autoantigen regulation, relevant for the early pathogenesis of TAMG and thymoma-associated autoimmune disorders. Our findings should be verified in larger cohorts and with functional and histological validation.</p>

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Promoter CpG island hypomethylation and overexpression of molecules homologous to the muscle autoantigens acetylcholine receptor and ryanodine receptor in thymoma epithelial cells associated with myasthenia gravis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Yu Hong,
  • Hai-Feng Li,
  • Yanjun Guo,
  • Lei Liu,
  • Geir Olve Skeie,
  • Jiawei Wang,
  • Nils Erik Gilhus

摘要

Background

Thymoma-associated myasthenia gravis (TAMG) represents the paraneoplastic subtype of MG and is characterized by autoantibodies against skeletal muscle proteins, such as acetylcholine receptor (AChR), titin, and ryanodine receptor (RyR). Thymic epithelial cells of TAMG patients overexpress neuronal and neuromuscular genes that code for MG autoantigen epitopes. This may contribute to the autoimmune breakdown in TAMG patients. This study explored whether such aberrant expression of autoimmune epitopes is regulated by their promoter CpG methylation profiles.

Methods

The thymoma bulk RNA sequencing, single cell RNA sequencing, and DNA methylation data were collected from 40 TAMG and 96 non-MG thymoma patients using three independent cohorts. A novel algorithm using a multiple linear regression model was developed to examine the gene promoter CpG island methylation status in TAMG and non-thymoma MG patients. The correlation between promoter CpG island and RNA expression in the TAMG thymoma was explored.

Results

In both TAMG and non-MG thymoma, the global promoter CpG islands were hypomethylated and were negatively correlated with RNA expression. The CpG islands at promoters of muscle-like epitope genes, NEFM and RYR3, were significantly hypomethylated in TAMG thymoma and negatively correlated with mRNA expression in both a primary and a verification cohort. For MG antigen genes CHRNA1, TTN and RyR1, the CHRNA1 promoter CpG site methylation correlated negatively with CHRNA1 RNA expression. However, there was no difference in promoter methylation status between TAMG and non-MG thymomas. For the AIRE gene, the promoter CPG islands were significantly hypermethylated and negatively correlated with mRNA expression. Both bulk and single cell RNA sequencing showed that key genes involved in the DNA CpG methylation pathways, including DNMT1, UHRF1 and HDAC1, had a reduced expression in thymic epithelial cells of TAMG thymoma.

Conclusions

Our results indicate that the aberrant overexpression of muscle-like epitopes in TAMG might be driven by CpG island hypomethylation. This represents a novel mechanism for intrathymic autoantigen regulation, relevant for the early pathogenesis of TAMG and thymoma-associated autoimmune disorders. Our findings should be verified in larger cohorts and with functional and histological validation.