Adverse maternal environments perturb hepatic DNA methylome and transcriptome prior to the adult-onset non-alcoholic fatty liver disease in mouse offspring [RRBS]
Exposure to adverse early-life environment (AME) increases the incidence of developing adult-onset non-alcoholic fatty liver disease (NAFLD). DNA methylation has been postulated to link AME and late-onset diseases. The objective was to investigate whether and to what extent hepatic DNA methylome was perturbed prior to the development of NAFLD in offspring exposed to AME in mice. AME constituted maternal western diet and late-gestational stress. Male offspring livers at birth (d0) and weaning (d21) were used for evaluating DNA methylome and transcriptome using reduced representation of bisulfite sequencing and RNA-seq, respectively. We found AME caused 5,879 differentially methylated regions (DMRs) and zero differentially expressed gene (DEG) at d0, and 2,970 and 123, respectively at d21. Majority of the DMRs were distal from gene transcription start sites and did not correlate with DEGs. The DEGs at d21 were significantly en-riched in GO biological processes characteristic of liver metabolic functions. In conclusion, AME drove changes in hepatic DNA methylome which preceded perturbations in the hepatic metabolic transcriptome, which preceded the onset of NAFLD. We speculate that subtle impacts in dynamic enhancers lead to long-range regulatory changes that manifest over time as gene network alter-nations to increase the incidence of NAFLD later in life. Overall design: Comparative analysis of RRBS and RNA-seq data from the livers of C57bl/6 male mouse offspring (at birth and weaning) of dams experienced adverse maternal