Epigenetics of Gene-Environment Interactions in a Mouse-Diet Model

Abstract

Epigenetics lies at a crucial intersection between genetic background and environmental influence. However, studying the nature of this mediating role in gene-environment interactions is challenging in humans due to extreme variation and lack of reproducibility in both genotypes and exposures. To address these shortcomings, we examined DNA CpG methylation and gene expression in a mouse model project using whole genome bisulfite sequencing and RNA-Seq. In our design, we combine multiple inbred strains with diets reflecting common human nutrition. We discover that diet-induced methylation and expression changes are strikingly disparate between genotypes, with only a small partiality of conserved metabolic genes and pathways. Genotype-dependent methylation is not linked to cis-acting sequence, implying trans and/or complex effects in their mechanism. Our findings have profound implications for the future of gene-environment epigenetic studies, particularly concerning recombinant inbred animal strains. As a companion to this diet experiment, we also discuss the technical challenges of experimental designs involving DNA methylation in multiple distant inbred strains, which differ in their CpG landscapes. Furthermore, we present the novel tools and strategies we developed in order to handle bisulfite alignment, methylation estimation, and differential analysis for such designs, and which can similarly be applied towards future methylation experiments