Exciting new research from our team at VUGENE and our collaborators at Corewell Health and Acibadem University reveals key epigenetic insights into a common but under-recognized cause of dementia: Vascular Cognitive Impairment (VCI).
By examining the superior parietal brain region in VCI patients and healthy controls, our team discovered four major insights:
A Dominant Pattern of Gene Silencing: We identified 3,601 significantly altered DNA methylation sites, with a remarkable 82% showing increased hypermethylation in the VCI group.
Key Genes are Affected: Epigenetic modifications impact crucial genes like MTCH2, DPRX, and DENND4A, which are linked to neuronal health, vascular integrity, and dementia risk.
Striking Differences Between Sexes: The epigenetic landscape of VCI is not one-size-fits-all.
- Males showed far more methylation changes (191,162 sites) concentrated in vascular regulation pathways.
- Females showed fewer changes (4,645 sites) enriched in pathways for neuronal development and synaptic plasticity.
A New Link to Lysosomal Dysfunction: Analysis of Differentially Methylated Regions (DMRs) spotlighted the gene RAB12, connecting lysosomal dysfunction to both cognitive and vascular deterioration in VCI.
The Bioinformatics Behind the Breakthrough
Our advanced bioinformatics approach was essential to these discoveries. By combining the analysis of individual methylation sites (DMCs), larger genomic regions (DMRs), and pathway enrichment (GSEA), we gained a comprehensive view of VCI’s molecular signatures.
We also successfully adapted the RUVseq method to control for technical variation and hidden confounders in our data. Notably, the primary confounder vector this method identified (RUVg) was significantly correlated with the neuron proportion in the samples. This allowed us to use this single vector in our linear models to account for both cellular composition and other unwanted variables, preserving statistical power and ensuring our results were robust.
Why does this matter?
These findings could pave the way for new biomarkers and personalized therapies targeting both vascular and neuronal aspects of VCI. This is just the beginning — multi-omics approaches could bring us even closer to fully understanding the complex biological mechanisms behind this condition.
Sangeetha Vishweswaraiah, Nazia Saiyed, Abdullah Khalid, Milda Milčiūtė, Miglė Gabrielaitė, Ceyda Buyuker, Boran Aksakal, Lorena Gomes, Juozas Gordevičius, Ali Yilmaz, Stewart F. Graham. Molecular Neurobiology, 1-15.
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Written by: Milda Milčiūtė
Cover image credits: Teeradej / Adobe Stock