Martínez-López Javier, Ortiz-Fernandez Lourdes, Estupiñán-Moreno Elkyn, Kerick Martin, Andrés-León Eduardo, Terron-Camero Laura C, Carnero-Montoro Elena, Barturen Guillermo, Beretta Lorenzo, Almeida Isabel, Alarcón-Riquelme Marta E, Ballestar Esteban, Acosta-Herrera Marialbert, Martín Javier
Institute of Parasitology and Biomedicine López-Neyra, Consejo Superior de Investigaciones Científicas and Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
Institute of Parasitology and Biomedicine López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
Arthritis Rheumatol. 2025 Apr;77(4):439-449. doi: 10.1002/art.43044. Epub 2024 Dec 12.
Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study.
We analyzed DNA methylation data from whole-blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) <0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels.
This analysis yielded 525 DMPs enriched in immune-related pathways, with leukocyte cell-cell adhesion being the most significant (FDR = 4.91 × 10), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil-related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development.
Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.
非遗传因素影响系统性硬化症（SSc）的发病机制，这突出了表观遗传学在该疾病中的重要作用。我们旨在通过全基因组关联研究揭示与SSc相关的DNA甲基化异常。
我们分析了179例SSc患者和241例未受影响个体全血样本的DNA甲基化数据，以识别错误发现率（FDR）<0.05的差异甲基化位点（DMP）。这些结果进一步与同一患者的RNA测序数据整合，以评估其功能后果。此外，我们研究了DNA甲基化变化对转录因子的影响，并分析了甲基化改变与基因表达谱及血清蛋白水平之间的关系。
该分析产生了525个富集于免疫相关途径的DMP，其中白细胞细胞间黏附最为显著（FDR = 4.91×10），通过整合甲基化组和转录组数据，整合素被优先考虑。此外，通过这种综合方法，我们观察到中性粒细胞相关途径的富集，突出了这种髓系细胞类型在SSc发病机制中的重要作用。此外，我们还发现了该疾病中涉及的新的促纤维化和促炎机制。最后，表观遗传和转录组特征的改变揭示了SSc中CCAAT/增强子结合蛋白转录因子家族的活性增加，这在髓系谱系发育中至关重要。
我们的研究结果揭示了该疾病表观遗传调控受损及其对基因表达的影响，确定了潜在临床应用的新分子，并增进了我们对SSc发病机制的理解。
