Decitabine-induced DNA methylation remodeling reveals targetable biological processes in gilthead seabream pituitary and liver explants

Abstract

Epigenetic manipulations have the potential to improve traits in farmed fish. To explore this opportunity in the gilthead seabream (Sparus aurata), the catalytic domains of five DNA methyltransferases (DNMTs) were predicted by homology modeling, and their interaction with the inhibitor 5-aza-2′-deoxycytidine (DAC) was assessed by docking, revealing that the inhibitor can bind all DNMTs with similar energy. Then, pituitary and liver explants from gilthead seabream were exposed to DAC for 24 h, and changes in genome-wide DNA methylation (RRBS) and gene expression (RNA-seq) were assessed. In the liver, functional enrichment revealed upregulation of ribosome biogenesis and protein synthesis, while mitochondrial functioning, genome stability, and DNA and amino acid metabolism were downregulated. Exposed pituitaries displayed upregulation of ribosomal biogenesis and protein synthesis, alongside mitochondrial functioning and genome stability. Nucleotide-level methylomes were obtained for the first time in this species, with hypomethylated sites observed in 3’UTRs, promoter regions, and introns of highly expressed genes across both tissues. A higher level of DNA methylation at exons was found in highly expressed genes in the liver. The seabream pituitary was more permissive to DNA methylation remodeling than the liver. Functional Epigenetic Module analysis revealed seven interactome hotspots in liver and four in pituitary, mostly related to protein trafficking and signal transduction in the liver, and mitochondrial functioning in the pituitary, indicating that these functions can potentially be targeted by epigenetic interventions in seabream. The data resources generated in our study may be used to explore novel avenues to boost seabream performance and welfare.