早期生命阶段的营养状况可能对动物的新陈代谢产生持久的影响，尽管这些长期效应的机制仍不清楚。表观遗传修饰被认为是在这一关键发育阶段编码早期生命营养记忆的主要候选机制。然而，这些表观遗传变化在何种程度上发生并持续的时间仍然不确定，这在一定程度上是由于直接刺激胎儿以特定营养物质在卵胎哺乳动物系统中的挑战。在本研究中，我们使用七彩鱼作为卵胎脊椎动物模型，建立了一种早期高脂饮食（HFD）模型。幼虫从孵化阶段（受精后一周）开始喂养HFD，持续六周，然后转为正常饮食（NC），直到成年阶段为止。我们研究了肝脏在这一时期的转录组和表观遗传状态的变化。我们发现，HFD引发了简单肝脏脂肪变性，并伴随肝脏转录组、染色质可访问性和组蛋白修饰的剧烈变化，尤其是在代谢基因方面。这些变化在长期NC后大部分逆转，表明肝细胞的表观遗传状态具有很高的可塑性。然而，我们发现了一定数量的基因组位点显示出非可逆的表观遗传变化，尤其是与细胞信号传导、肝纤维化和肝细胞癌相关的基因周围，暗示早期HFD喂养引发的肝细胞状态变化是持久的。总之，我们的数据显示早期HFD喂养会触发七彩鱼肝细胞中可逆和持久的表观遗传变化。我们的数据为营养规划的表观遗传机制提供了新的见解，并提供了非哺乳类脊椎动物早期HFD模型的长期表观遗传状态的综合图谱。© 2023. BioMed Central Ltd., part of Springer Nature.

The nutritional status during early life can have enduring effects on an animal's metabolism, although the mechanisms underlying these long-term effects are still unclear. Epigenetic modifications are considered a prime candidate mechanism for encoding early-life nutritional memories during this critical developmental period. However, the extent to which these epigenetic changes occur and persist over time remains uncertain, in part due to challenges associated with directly stimulating the fetus with specific nutrients in viviparous mammalian systems.In this study, we used medaka as an oviparous vertebrate model to establish an early-life high-fat diet (HFD) model. Larvae were fed with HFD from the hatching stages (one week after fertilization) for six weeks, followed by normal chow (NC) for eight weeks until the adult stage. We examined the changes in the transcriptomic and epigenetic state of the liver over this period. We found that HFD induces simple liver steatosis, accompanied by drastic changes in the hepatic transcriptome, chromatin accessibility, and histone modifications, especially in metabolic genes. These changes were largely reversed after the long-term NC, demonstrating the high plasticity of the epigenetic state in hepatocytes. However, we found a certain number of genomic loci showing non-reversible epigenetic changes, especially around genes related to cell signaling, liver fibrosis, and hepatocellular carcinoma, implying persistent changes in the cellular state of the liver triggered by early-life HFD feeding.In summary, our data show that early-life HFD feeding triggers both reversible and persistent epigenetic changes in medaka hepatocytes. Our data provide novel insights into the epigenetic mechanism of nutritional programming and a comprehensive atlas of the long-term epigenetic state in an early-life HFD model of non-mammalian vertebrates.© 2023. BioMed Central Ltd., part of Springer Nature.