Neuroepigenetic programming by the maternal environment: part A—epigenome-wide DNA methylation profile in the offspring’s olfactory bulb following preconceptional weight loss in mice

Experimental models and epidemiological data suggest that the maternal nutritional environment during gestation plays important roles in brain development with consequences on cognitive health. Epigenetic marks, such as methylation and histone modifications, are likely to be involved in this programming, but little addressed the impact of maternal metabolism at the preconceptional period. In mice, we recently demonstrated lasting effects of a maternal preconceptional weight loss on metabolic outcomes and behaviors related to food intake in the male offspring, exhibiting a reduction in olfactory sensitivity, along with a lack of fasting-induced olfactory-based motivation. To evaluate if this effect was driven by epigenetic modifications in the olfactory bulb, we profiled brain DNA methylation, a fundamental process in mediating the relation between early life environment and long-term behaviors in mice according to the maternal status. Using oxidative reduced representation bisulfite sequencing to specifically target 5mC in mice exposed to preconceptional weight loss versus controls, we identified 11,055 differentially methylated cytosines and 150 differential methylated regions (DMRs) located in 111 genes in the olfactory bulb, a main region involved in odor processing and integration. Among the cytosines differentially methylated, half were hypermethylated. Methylation remodeling according to the maternal group preferentially affected noncoding intragenic regions, distal regulatory elements, and open sea CpGs, while promoter CpG islands remain relatively resistant to modification in DNA methylome. The functional annotation of DMRs pointed out genes related to histones kinases, energy signaling, synaptic function, and cellular differentiation, suggesting that targeted methylation changes may simultaneously influence epigenetic regulation, metabolism, and neurobiology. Thanks to a single-base analysis of differential methylated CpGs, we present novel evidence that the maternal dietary environment prior to conception exerts maternally-driven epigenetic effects, markedly altering 5-methylcytosine patterns in the adult offspring brain. This long-lasting remodeling of the offspring’s olfactory bulb methylome may underlie the described alterations in olfactory-driven behaviors of offspring born to WL mother.