Hepatic transcriptome and epigenome in response to high-fat diet

Nutritional state in early life can pose life-long effects on the metabolism of animals, although the mechanism underlying long-term nutritional memory is unclear. Epigenetic modifications are one of the prime candidates for early life nutritional memories, but it is still uncertain to what extent the epigenetic state changes and persists, partly due to difficulties in direct nutritional stimulation on fetuses in mammals. Using medaka as an oviparous vertebrate model, here we established an early-life high-fat diet (HFD) model, in which fish were fed HFD from hatching stages for six weeks, followed by normal chow (NC) for eight weeks until adult stage, and traced genome-wide transcriptomic and epigenetic state of the liver. We found that HFD induces fatty liver phenotypes, accompanied by drastic changes in hepatic transcriptome, chromatin accessibility, and histone modifications. These changes were largely recovered after the long-term NC, demonstrating the high plasticity of epigenetic state in hepatocytes. However, we found a few genomic loci showing persistent epigenetic changes, implying the latent changes in liver triggered by early-life HFD feeding. Our data provide a comprehensive atlas of long-term epigenetic state in early-life HFD model of non-mammalian vertebrates, and insights into the epigenetic mechanism of nutritional programming.