Patil Vibha, Cruz-Granados Pablo, Cara Francisca E, Amor-Dorado Juan Carlos, Aran Ismael, Soto-Varela Andres, Perez-Carpena Patricia, Lopez-Escamez Jose Antonio
Meniere's Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, The University of Sydney, Sydney, NSW, Australia.
Otology & Neurotology Group CTS495, Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, ibs.GRANADA, Granada, Universidad de Granada, Granada, Spain.
J Mol Med (Berl). 2025 Aug 6. doi: 10.1007/s00109-025-02581-6.
Meniere disease (MD) is a cochleo-vestibular syndrome defined by episodes of vertigo associated with tinnitus and sensorineural hearing loss. While MD immune response has been linked to autoinflammation and type 2 cytokines, other molecular mechanisms such as DNA methylation have an emerging yet underexplored role in MD pathophysiology.To understand the role of DNA methylation in MD, we performed whole-genome bisulphite sequencing in MD patients (n = 40) and controls (n = 13) and used differentially methylated cytosines (DMCs) to define clusters, cell types, and biochemical pathways in MD. We found three MD subclusters: Cluster 1 (40% of patients) and Cluster 3 (25%) showed DMC profiles against controls, while Cluster 2 (35%) did not. Significant DMCs from Cluster 1 and Cluster 3 versus Control analysis were annotated to 3033 and 59 unique genes, respectively. Each cluster showed a different gene enrichment; however, the KDMB4 gene had significant upregulated DNA accessibility in a complementary ATAC-seq dataset and showed significant DMCs in both Cluster 1 and Cluster 3. DNA methylation patterns in MD reveal three clusters which are reflective of an underlying difference in pathways related to cytokine stimulus, immunity T-cell, and NK-cell pathways. KDMB4 emerges as a critical MD gene which deserves further research. KEY MESSAGES: We asked if DNA methylation can help understand Meniere's Disease (MD) pathophysiology. DNA methylomes group MD patients into three distinct sub-clusters. DNA methylation in MD reflect difference in pathways related to neurons and cytokine stimulus. The data shows KDMB4 emerging as a key gene that requires further multi-modal investigation.
梅尼埃病（MD）是一种耳蜗-前庭综合征，其特征为伴有耳鸣和感音神经性听力损失的眩晕发作。虽然MD的免疫反应与自身炎症和2型细胞因子有关，但DNA甲基化等其他分子机制在MD病理生理学中的作用正在显现，但尚未得到充分研究。为了了解DNA甲基化在MD中的作用，我们对MD患者（n = 40）和对照组（n = 13）进行了全基因组亚硫酸氢盐测序，并使用差异甲基化胞嘧啶（DMC）来定义MD中的簇、细胞类型和生化途径。我们发现了三个MD亚簇：簇1（40%的患者）和簇3（25%）显示出与对照组不同的DMC谱，而簇2（35%）则没有。簇1和簇3与对照组分析的显著DMC分别注释到3033个和59个独特基因。每个簇显示出不同的基因富集；然而，KDMB4基因在互补的ATAC-seq数据集中具有显著上调的DNA可及性，并且在簇1和簇3中均显示出显著的DMC。MD中的DNA甲基化模式揭示了三个簇，这反映了与细胞因子刺激、免疫T细胞和NK细胞途径相关的潜在途径差异。KDMB4作为一个关键的MD基因出现，值得进一步研究。关键信息：我们询问DNA甲基化是否有助于理解梅尼埃病（MD）的病理生理学。DNA甲基化组将MD患者分为三个不同的亚簇。MD中的DNA甲基化反映了与神经元和细胞因子刺激相关途径的差异。数据显示KDMB4作为一个关键基因出现，需要进一步进行多模式研究。
