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bioRxiv · 10.1101/2025.05.23.654932

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

Gibson, E. F.·Torres-Velarde, J. M.·Ensminger, D. C.·Moreno-Santillan, D. D.·Crocker, D. E.·Vazquez-Medina, J. P.
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Abstract

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 role 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 seal muscle cells in primary culture. We found that fasting transiently increases blood DNA methylation and that blood DNA methylation levels correlate with plasma cortisol. Hence, we then conducted bioinformatic analyses to identify regions in the elephant seal glucocorticoid receptor (GR) promoter that influence gene transcription through methylation (CPG islands). We identified one CpG island within the putative promoter region of GR gene. 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 hours decreased DNA methylation while upregulating pro-survival gene expression in seal myotubes. Our results show that whereas prolonged fasting transiently increases DNA methylation in elephant seal blood, sustained exposure to exogenous glucocorticoids decreases DNA methylation and activates a pro-survival transcriptional program in seal myotubes. Therefore, our results suggest that DNA methylation is a plastic, potentially cell-type-specific response that regulates gene expression in fasting seals. Summary statementDNA methylation is a plastic response to fasting and increased glucocorticoids in elephant seals. Our work underscores the role of epigenetic regulation of gene expression during energetically challenging conditions in seals and potentially other mammals.

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Gibson, E. F., Torres-Velarde, J. M., Ensminger, D. C., Moreno-Santillan, D. D., Crocker, D. E., Vazquez-Medina, J. P.. 2025-05-28. Prolonged fasting and glucocorticoid exposure drive dynamic DNA methylation in elephant seals. https://doi.org/10.1101/2025.05.23.654932

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