UC Irvine

The work in this presentation creates a completely novel dataset for exploring DNA methylation as a means for predicting epigenetic (biological) age and memory performance. In the first study, dorsal hippocampal (DHPC) tissue from young and aging mice, both male and female, was processed for reduced representation bisulfite sequencing (RRBS) to establish methylome signatures. We found aging male and female mice exhibited global hypomethylation, but diverging sex-dependent patterns in methylation enrichment specific to genomic context. Aging males displayed significant hypomethylation in 3’UTR regions while females displayed significant hypermethylation in the same region. In both sexes, hypomethylated regions were significantly associated with binding motifs integral to activity-dependent transcription. In a second study, male mice at five different ages underwent a memory updating behavior task followed by RRBS analysis of dorsal hippocampal tissue to investigate how methylation may correlate to age-related memory impairment. With this behavioral cohort, we created a highly accurate epigenetic age predictor, labeled an epigenetic clock. We also generated a second and third memory updating and testing behavior predictor, each with a unique set of CpG sites. DHPC DNA methylation correlation with behavior was strongest when tested for an original memory, but not an updated memory. Thus, this suggests that generation of behavior predictors may be time-dependent and strongest for retrieval of original information, influenced by methylation patterns in the dorsal hippocampus. In sum, we generated the first epigenetic clock, to our knowledge, specific to bulk tissue in the male mouse dorsal hippocampus. Our data suggests that separate but accurate behavior predictors of memory performance are a plausible and compelling link to age-related changes in DNA methylation.