Muroya Susumu, Ojima Koichi, Shimamoto Saki, Sugasawa Takehito, Gotoh Takafumi
Department of Animal Science and Welfare, Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-8580, Japan.
Division of Meat Animal and Poultry Research, NARO Institute of Livestock and Grassland Science, 2 Ikenodai, Tsukuba 305-0901, Ibaraki, Japan.
Int J Mol Sci. 2025 Aug 4;26(15):7540. doi: 10.3390/ijms26157540.
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 , , , and but lower in and . 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 , , , and were upregulated in the MUN fetal liver, suggesting involvement of the response in 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.
母体营养不良（MUN）会导致哺乳动物后代出现严重的代谢紊乱。在此，我们确定了组蛋白修饰在营养受限奶牛妊娠晚期胎儿肝脏基因表达中的作用，这是一个使用低营养（LN）和高营养（HN）条件建立的模型。染色质免疫沉淀测序结果表明，组蛋白3赖氨酸4三甲基化（H3K4me3）发生改变的基因与皮质醇合成与分泌、PPAR信号通路以及醛固酮合成与分泌有关。H3K27me3发生改变的基因与谷氨酸能突触和胃酸分泌有关。与HN胎儿相比，LN胎儿中、、和基因的启动子H3K4me3水平较高，而和基因的启动子H3K4me3水平较低。有趣的是，表达变化最大（>1.5倍）的基因表现出因H3K4me3水平升高或降低而预期的上调/下调；然而，在启动子CpG甲基化或H3K27me3与表达变化最大的基因集之间未观察到显著关系。此外，应激反应基因、、和在MUN胎儿肝脏中上调，表明该反应参与了激活。因此，H3K4me3可能在MUN诱导的生理适应中起关键作用，改变负责综合应激反应和全身能量代谢（尤其是循环脂蛋白脂肪酶调节）的肝脏基因表达。
