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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2024)

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.

    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2021)
    DNA methylation is a well-characterized epigenetic modification involved in numerous molecular and cellular functions. Methylation patterns have also been associated with aging mechanisms. However, how DNA methylation patterns change within key brain regions involved in memory formation in an age- and sex-specific manner remains unclear. Here, we performed reduced representation bisulfite sequencing (RRBS) from mouse dorsal hippocampus - which is necessary for the formation and consolidation of specific types of memories - in young and aging mice of both sexes. Overall, our findings demonstrate that methylation levels within the dorsal hippocampus are divergent between sexes during aging in genomic features correlating to mRNA functionality, transcription factor binding sites, and gene regulatory elements. These results define age-related changes in the methylome across genomic features and build a foundation for investigating potential target genes regulated by DNA methylation in an age- and sex-specific manner.
      Cover page: Examining age-dependent DNA methylation patterns and gene expression in the male and female mouse hippocampus
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2024)
      A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozymes self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the Cpeb3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.
        Cover page: Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs and enhances object location memory.
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