Prolonged fasting and glucocorticoid exposure drive dynamic DNA methylation in northern elephant seals.

Northern elephant seals experience prolonged fasting while breeding, molting and undergoing postnatal development. Fasting elephant seals adjust neuroendocrine function and gene expression to cope with potentially detrimental effects associated with extended fasting. DNA methylation alters gene expression by modulating accessibility to regions necessary to initiate transcription. The effect of fasting and glucocorticoids on DNA methylation in elephant seals is understudied. We evaluated whether fasting alters global blood DNA methylation, the potential correlation between increased glucocorticoids and methylation, and the effects of glucocorticoids on DNA methylation in cultured northern elephant seal muscle cells. We found that fasting transiently increases blood DNA methylation and that blood DNA methylation levels correlate with plasma cortisol. We then conducted bioinformatic analyses to identify regions in the northern elephant seal glucocorticoid receptor (GR) promoter that influence gene transcription through methylation (CpG islands). We identified one CpG island within the putative GR promoter. Methylation in this region, however, was unaffected by prolonged fasting. We then investigated whether exogenous glucocorticoids alter DNA methylation and gene expression profiles in seal muscle cells in primary culture (myotubes). Exposure to glucocorticoids for 12 or 48 h decreased DNA methylation while upregulating pro-survival gene expression in northern elephant seal muscle cells. Our results show that whereas prolonged fasting transiently increases DNA methylation in northern elephant seal blood, sustained exposure to exogenous glucocorticoids decreases DNA methylation and activates a pro-survival transcriptional program in seal muscle cells. Therefore, our results suggest that DNA methylation is a plastic, potentially cell type-specific response that regulates gene expression in fasting northern elephant seals.