Poster #032, University of California, San Francisco
Study of How DNMT1 Mutations Can Lead to Neurodegeneration
Mentors: Jing Wang, PhD and Xinxu Xu, PhD
DNMT1 is best known for maintaining DNA methylation, while pathogenic DNMT1 mutations can cause late-onset neurodegeneration. To investigate the cell-type-specific effects of the Dnmt1 A560V mutation in the brain, we will analyze previously generated single-nucleus RNA-sequencing data from the mouse prefrontal cortex. After quality control, normalization, clustering, and UMAP visualization using Seurat, major cortical cell types will be annotated based on established marker genes. Cell-type proportions, differential gene expression, and pathway activity will then be compared among wild-type, heterozygous, and homozygous mice. We anticipate that the major cortical cell populations will be preserved across genotypes, whereas mutant mice will exhibit cell-state-specific transcriptional alterations. In particular, excitatory neurons are expected to show increased mitochondrial dysfunction and oxidative stress signatures, together with reduced expression of genes involved in synaptic function. Changes in glial activation may also be detected in microglia and astrocytes. These analyses will identify the cortical cell types most strongly affected by the Dnmt1 A560V mutation and provide insight into how altered neuronal metabolism, cellular stress, and neuroinflammatory responses may contribute to neurodegeneration. The findings may guide subsequent validation using immunostaining, quantitative PCR, and independent single-cell datasets.