Whole genome DNA methylation profles defne Meniere’s disease subclusters

Abstract

Meniere disease (MD) is a cochleo-vestibular syndrome defned by episodes of vertigo associated with tinnitus and sensorineural hearing loss. While MD immune response has been linked to autoinfammation 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 diferentially methylated cytosines (DMCs) to defne clusters, cell types, and biochemical pathways in MD. We found three MD subclusters: Cluster 1 (40% of patients) and Cluster 3 (25%) showed DMC profles against controls, while Cluster 2 (35%) did not. Signifcant DMCs from Cluster 1 and Cluster 3 versus Control analysis were annotated to 3033 and 59 unique genes, respectively. Each cluster showed a diferent gene enrichment; however, the KDMB4 gene had signifcant upregulated DNA accessibility in a complementary ATAC-seq dataset and showed signifcant DMCs in both Cluster 1 and Cluster 3. DNA methylation patterns in MD reveal three clusters which are refective of an underlying diference in pathways related to cytokine stimulus, immunity T-cell, and NK-cell pathways. KDMB4 emerges as a critical MD gene which deserves further research.