Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams

Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin immunoprecipitation sequencing results show that genes with an altered trimethylation of histone 3 lysine 4 (H3K4me3) are associated with cortisol synthesis and secretion, the PPAR signaling pathway, and aldosterone synthesis and secretion. Genes with the H3K27me3 alteration were associated with glutamatergic synapse and gastric acid secretion. Compared to HN fetuses, promoter H3K4me3 levels in LN fetuses were higher in <i>GDF15</i>, <i>IRF2BP2</i>, <i>PPP1R3B</i>, and <i>QRFPR</i> but lower in <i>ANGPTL4</i> and <i>APOA5</i>. Intriguingly, genes with the greatest expression changes (>1.5-fold) exhibited the anticipated up-/downregulation from elevated or reduced H3K4me3 levels; however, a significant relationship was not observed between promoter CpG methylation or H3K27me3 and the gene set with the greatest expression changes. Furthermore, the stress response genes <i>EIF2A</i>, <i>ATF4</i>, <i>DDIT3</i>, and <i>TRIB3</i> were upregulated in the MUN fetal liver, suggesting involvement of the response in <i>GDF15</i> activation. Thus, H3K4me3 likely plays a crucial role in MUN-induced physiological adaptation, altering the hepatic gene expression responsible for the integrated stress response and systemic energy metabolism, especially circulating lipoprotein lipase regulation.