Gibson Emily F, Torres-Velarde Julia María, Ensminger David C, Moreno-Santillán Diana D, Crocker Daniel E, Vázquez-Medina José Pablo
Department of Integrative Biology, University of California, Berkeley, 3040 Valley Life Sciences Building #3140, Berkeley, CA 94720-3140, USA.
Department of Biology, Sonoma State University, Rohnert Park, CA 94928, USA.
J Exp Biol. 2025 Aug 1;228(15). doi: 10.1242/jeb.250046. Epub 2025 Jul 25.
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.
北象海豹在繁殖、蜕皮和产后发育期间会经历长时间的禁食。禁食的象海豹会调整神经内分泌功能和基因表达，以应对与长期禁食相关的潜在有害影响。DNA甲基化通过调节转录起始所需区域的可及性来改变基因表达。禁食和糖皮质激素对象海豹DNA甲基化的影响尚未得到充分研究。我们评估了禁食是否会改变整体血液DNA甲基化、糖皮质激素增加与甲基化之间的潜在相关性，以及糖皮质激素对培养的北象海豹肌肉细胞中DNA甲基化的影响。我们发现禁食会短暂增加血液DNA甲基化，并且血液DNA甲基化水平与血浆皮质醇相关。然后我们进行了生物信息学分析，以确定北象海豹糖皮质激素受体（GR）启动子中通过甲基化（CpG岛）影响基因转录的区域。我们在假定的GR启动子内鉴定出一个CpG岛。然而，该区域的甲基化不受长期禁食的影响。然后我们研究了外源性糖皮质激素是否会改变原代培养的海豹肌肉细胞（肌管）中的DNA甲基化和基因表达谱。在北象海豹肌肉细胞中，暴露于糖皮质激素12或48小时会降低DNA甲基化，同时上调促生存基因的表达。我们的结果表明，虽然长期禁食会短暂增加北象海豹血液中的DNA甲基化，但持续暴露于外源性糖皮质激素会降低DNA甲基化，并在海豹肌肉细胞中激活促生存转录程序。因此，我们的结果表明，DNA甲基化是一种可塑性的、可能具有细胞类型特异性的反应，可调节禁食的北象海豹中的基因表达。
