dc.description.abstract | Background: Epigenetic memory involves heritable gene expression changes without DNA sequence alterations, impacting cellular functions long after the initial triggers have ceased. The impact of obesity on pancreatic function has been well documented, but epigenetic memory in this context remains unclear.
Objective: To explore epigenetic memory of obesity in the pancreas.
Methods: Pancreata from mice with three dietary histories (obese, post-obese, lean) were analyzed using RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq) for histone H3 lysine 27 acetylation (H3K27ac), and assay for transposase-accessible chromatin using sequencing (ATAC-seq), in which Tn5 transposase binding sites were used to assess chromatin accessibility. Results of differential gene expression, promoter accessibility, and histone acetylation analyses were compared. Gene set enrichment analysis (GSEA) was performed based on these results, and the identified epigenetic memory (EM) gene sets and their core genes were characterized.
Results: Few individual genes were differential (𝑃adj < 0.05) in H3K27ac and Tn5 across all groups and in RNA-seq between post-obese and lean mice. GSEA revealed 240 EM gene sets, enriched in both obese and post-obese compared to lean, predominantly in Tn5. EM gene sets included 36 related to lipid metabolism, 29 to cellular respiration, and others related to RNA processing, nucleotide metabolism, translation, protein processing, mitosis, and chromatin. EM core genes had high promoter counts and showed subtle yet consistent and widespread, highly correlated changes in Tn5 and H3K27ac but not in RNA. EM core genes were upregulated in obese compared to lean in both Tn5 and H3K27ac; in post-obese, they were downregulated compared to obese but upregulated compared to lean in Tn5, while H3K27ac showed reversed trends.
Conclusion: Epigenetic memory of obesity in the pancreas manifests as subtle, coordinated changes in promoter accessibility, not continuous gene expression changes. Histone acetylation, contrary to its general characterization as the upstream regulator of chromatin accessibility, does not act as such in this context. Bivalent chromatin may instead mediate the latent memory. The findings need replication, and further studies could investigate bivalency, DNA methylation, nucleosome occupancy, promoter-enhancer interaction, and temporal changes post-intervention. | |