Abstract 14166: Epigenetic Biomarkers Correlate With Post-stroke Long-term Memory Recovery

Abstract

Introduction: Epigenetic markers including 5-metylcytosine (5mC) can reflect disease severity and treatment effect. Stroke is a multifactorial disease causing aberrant DNA methylation (DNAm) and memory damage. Hypothesis: Models built for 5mC biomarker panel signatures may be useful for quantitative prediction of post-stroke long-term memory recovery in response to treatment. Methods: Stroke was induced with a middle cerebral artery occlusion (MCAO)(18 rats: sham(6), stroke(6), and stroke with treatment (6)). Xe-liposomes were intravenously administrated repetitively for 3 days after MCAO. At day 35, memory was assessed and scaled using a novel objective recognition test. Brain hippocampus and cortex tissue samples were prepared for whole-genome bisulfite sequencing (WGBS) to generate quantitative DNA methylation datasets in response to repetitive intermittent Xe administration. The resulting WGBS data were evaluated and quantitatively associated with memory recovery. Results: A post-stroke long-term memory outcome model was generated with scaled data using the following inputs: (1) good recovery, (2) moderate recovery, (3) edge, (4) light damage, and (5) severe damage. Differential DNAm 5mC analysis was performed comparing MCAO affected hemisphere with sham and Xe-treated samples. Initial 5mC differential analysis identified 6,175 (Cortex), and 9,037 (Hippocampus) CpG sites that were different between groups. Subsequently the LASSO algorithm was applied and selected 22 CpG sites that correlated with the long-term memory recovery scale. PCA analysis using the 22 CpGs demonstrated separation of memory outcomes. We have also built a predictive linear regression model of the 22 CpGs to assess memory loss or recovery in response to treatment. Analysis showed 7 out of 22 CpGs are conserved in humans (orthologs) for 30 bp regions. Conclusions: Epigenetic 5mC marker panels have the potential for quantitating post-stroke memory damages/recovery.