Early life diet conditions the molecular response to post-weaning protein restriction in the mouse

Abstract

BackgroundEnvironmental influences fluctuate throughout the life course of an organism. It is therefore important to understand how the timing of exposure impacts molecular responses. Herein, we examine the responses of two key molecular markers of dietary stress, namely variant-specific methylation at ribosomal DNA (rDNA) and small RNA distribution, including tRNA fragments, in a mouse model of protein restriction (PR) with exposure at pre- and/or post-weaning.ResultsWe first confirm that pre-weaning PR exposure modulates the methylation state of rDNA in a genotype-dependent manner, whereas post-weaning PR exposure has no such effect. Conversely, post-weaning PR induces a shift in small RNA distribution, but there is no effect in the pre-weaning PR model. Intriguingly, mice exposed to PR throughout their lives show neither of these two dietary stress markers, similar to controls.ConclusionsThe results show that the timing of the insult affects the nature of the molecular response but also, critically, that ‘matching’ diet exposure either side of weaning eliminates the stress response at the level of rDNA methylation and small RNA in sperm.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0516-5) contains supplementary material, which is available to authorized users.

Characterization of Different Commercial Dietary Supplements in the Peri-Weaning Period on Consumption and Growth Performance in C57Bl/6J Mice

“…The Gel's top ingredient is peanut butter which is high in fat followed by molasses, a simple sugar. The low ADG in the Gel-treated groups is likely related to the preferential consumption of the supplement which is low in protein, since protein restriction is known to slow growth rates in mice [41]. This finding is consistent with previous reports utilizing this gel where decreased survival rates and lower average birth weights were observed with the conclusion that this gel was probably not suitable for use with breeders and pups [19].…”

“…Facilities that routinely provide standard diet on the cage floor to weanlings may experience similar pup support because of improved accessibility, however experimental evaluation is needed for confirmation since differences in pellet texture/hardness have been previously shown to affect growth [42]. There may be cost and convenience advantages to using Chow over Dough, but also a scientific preference for Chow since mice are not exposed to higher levels of fat and simple sugars early in life that may lead to persistent behavioral change or metabolic alteration [41,[43][44][45][46][47]. The persistent increased weight in male pups treated with Dough as compared with controls (p = 0.0476) suggests there is impact of this supplementation beyond the intended peri-weaning period.…”

The peculiar genetics of the ribosomal DNA blurs the boundaries of transgenerational epigenetic inheritance

“…Unequal sister chromatid exchange in the germ line would of course generate a complementary chromosome with a reduced rDNA array (Tartof 1974;Stults et al 2008). Recent data show that alteration of insulin/insulin-like signaling can cause reductions to rDNA copy number in individuals and their offspring, as can extreme dietary stress (Aldrich and Maggert 2015;Holland et al 2016;Danson et al 2018). Environmental stresses may also lead to wildly variant rDNA copy numbers (Schneeberger and Cullis 1991;Kwan et al 2016).…”

Mechanisms of epigenetic inheritance of variable traits through the germline

“…For some of these studies, profiling of small RNAs from spermatozoa of affected mice has revealed changes in content that correlate with the response. A change reported by several studies is a change in the abundance of tRNA fragments in sperm of affected male mice (Sharma et al 2016, Danson et al 2018, Zhang et al 2018b. It has been proposed that male gametes gain tRNA fragments and other small RNAs as they pass through the epididymis (Sharma et al 2016(Sharma et al , 2018.…”