(452) Fetal liver epigenetic and transcriptomic alterations by a maternal high-fat diet exposure in Japanese macaques

Objective: Human studies and experimental primate models have demonstrated that a maternal high-fat diet (mHFD) during pregnancy leads to persistent changes in her offspring's immunologic, metabolic, and microbiome profiles. Herein, we utilized our primate model to investigate how this occurs in utero. We hypothesized that impaired metabolic transcriptomic and epigenomic signatures would be detectible in the fetal liver tissue by the beginning of the 3^rd trimester.

Study Design: After conception, Japanese macaques were fed a control diet (N=3), mHFD (N=8), mHFD with resveratrol, an HDAC inhibitor at 480 mg/day (mHFRes; n=8), or switched from mHFD to control diet just before conception (mHFRev; N=3). At gestational day 130 (the human equivalent of 32 weeks), fetal livers were dissected and processed for both bulk RNA-seq and ChIP-seq.

Results: Differential expression revealed 154 fetal gene transcripts were significantly differentially expressed in response to mHFD (-2< log₂(fold-change >2; p < 0.05) (Fig. 1b). ChIP-seq identified altered epigenetic landscapes (p < 0.05) for active chromatin markers H3K14ac (149 genes) and H3K4me3 (1,090) and repressive marks H3K9me3 (309) and H3K27me3 (8,567) (Fig. 1b). Comparing the significantly differentially expressed transcripts with the genes that had significant changes in their histone marks yielded high-confidence histone-code modifiable genes of interests (Fig. 2). The metabolic pathways of glyoxylate, dicarboxylate, tryptophan, tyrosine, starch, sucrose, and thiamine were significantly impacted (f < 0.05, after controlling for multiple comparisons; KEGG).

Conclusion: This study provides a high-resolution map of mHFD-driven changes to the fetal hepatic histone code, which subsequently alter the gene expression of crucial metabolic pathways. Given the stability of these histone code modifications over time, these findings provide a vital link between maternal feeding and her offspring’s metabolic epigenetic landscape.