Refeeding with different levels of dietary carbohydrate modulates epigenetic stability through global DNA (de)methylation and histone modifications in juvenile and adult Nile tilapia ( <i>Oreochromis niloticus</i> )

The Nile tilapia (<i>Oreochromis niloticus</i>) exhibits a strong metabolic response to dietary carbohydrates (CHO). Short-term refeeding after fasting with a high-carbohydrate (HC) diet has been shown to modulate CHO metabolism, but the role of epigenetic regulation in this response remains unclear. This study investigated how short-term refeeding with either a HC [639.2 g kg^-1 diet]/low-protein [164.9 g kg^-1 diet] (HC/LP) diet or a low-CHO [47.4 g kg^-1 diet]/high-protein [607.9 g kg^-1 diet] (LC/HP) diet influences global DNA methylation and demethylation, histone modifications, and mRNA levels of epigenetic regulators in the liver and muscle of juvenile and adult Nile tilapia. Following a 4-day fasting period, fish were refed for 4 days with either HC/LP or LC/HP diets. Compared to the fasted state, refeeding with either diet altered epigenetic markers by: (1) decreasing hepatic global DNA 5-mC oxidative derivatives-5-hmdC in juveniles, and both 5-hmdC and 5-cadC in adults; (2) inducing histone hypermethylation and/or hyperacetylation - H3K9ac (hepatic) and H3K36me3 (muscular) in juveniles, and H3K9me3 and H3K9ac (muscular) in adults; and (3) promoting expression of enzymes related to DNA hypermethylation (upregulated <i>dnmt</i>, downregulated <i>tet</i>) and histone hypermethylation/acetylation (upregulated <i>setd1b</i>, <i>kmt2, suv39h1b</i>; downregulated <i>kdm4, sirt5</i>). Diet-specific effects included hepatic H3K36 hypomethylation and H3K9 hypoacetylation in juveniles fed HC/LP, accompanied by upregulation of <i>kdm4b, kdm4c</i>, and <i>sirt5</i>. In adults, HC/LP refeeding induced muscular DNA hypomethylation and H3K9 hypoacetylation, associated with upregulation of <i>tet, sirt2</i>, and <i>sirt5</i>. Refeeding following fasting induced histone hypermethylation and/or hyperacetylation, while HC refeeding was particularly associated with muscular global DNA hypomethylation and histone hypoacetylation/methylation.