Integrative whole-genome methylation and transcriptome analysis reveals epigenetic modulation of glucose metabolism by dietary berberine in blunt snout bream (Megalobrama amblycephala)

The present research was designed to explore the epigenetic mechanism by which dietary berberine (BBR) affects glucose metabolism in fish. Blunt snout bream (Megalobrama amblycephala) is susceptible to disturbances in glucose metabolism when subjected to prolonged high-carbohydrate diets. This study aimed to elucidate whether BBR can enhance glucose regulation in M. amblycephala via modulating DNA methylation levels. Fish (average weight of 20.36 ± 1.44 g) were administered a normal-carbohydrate diet (NC, 30 % carbohydrate), a high-carbohydrate diet (HC, 43 % carbohydrate), or a high-carbohydrate diet supplemented with 50 mg/kg berberine (HB) for 10 weeks. Subsequently, global DNA methylation level, whole-genome bisulfite sequencing (WGBS), RNA-seq, bisulfite sequencing PCR, and real-time quantitative PCR were employed to analyze the DNA methylation patterns and transcription results of the liver genome. The findings indicated that high carbohydrate diets induced glucose metabolism disorders in M. amblycephala, whereas BBR mitigated these metabolic disturbances by reducing methylation levels. WGBS results revealed that CG-type cytosine methylation predominated, and that DNA methylation mainly occurred in promoter, intron, and exon regions. Furthermore, analyses demonstrated a negative correlation between DNA methylation around the transcriptional start site and gene expression levels for 47 genes. Functional enrichment analysis revealed that these genes were associated with 60 KEGG pathways, including 12 genes implicated in the amelioration of insulin resistance, reduction of gluconeogenesis, and maintenance of glucose homeostasis. Consequently, we generated a comprehensive catalog of liver DNA methylation in M. amblycephala, which provides a foundational framework for future investigations into the epigenetic regulation of glucose metabolism by BBR.