Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice

Abstract

A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA). This epigenetic response remains into adulthood and is restricted to rDNA copies associated with a specific genetic variant within the promoter. Related effects are also found in models of maternal high-fat or obesogenic diets. Our work identifies environmentally induced epigenetic dynamics that are dependent on underlying genetic variation and establishes rDNA as a genomic target of nutritional insults.

The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

“…These insights, together with the understanding of how immune cells alter their epigenomes in reaction to or to contribute to a diseased environment (Pagani 2016, Paul 2016, Santana and Spicuglia 2016, Stunnenberg 2016, and how the epigenomic changes are established by environmental cues (Holland, Lowe et al 2016), will likely lead to new biomarkers for a better diagnosis and estimation of prognosis, as well as improved epi-drug based treatments and outcomes for a plethora of disease states. A present example of epigenomic analysis that may lead to testable clinical intervention is the reversal of endotoxininduced tolerance in macrophages (Stunnenberg 2016).…”

DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line

“…Additionally, this outcome was specifically dependent on the presence of the A-allele from a neighboring C/A SNP at position −104 (Holland et al 2016). The study represents an example of an epiallele with transcriptional activity and resulting phenotypic consequences dependent on both early life exposure and genetics (Holland et al 2016). This result also highlights the important notion that epigenetics, including DNA methylation, not only reflects environmental interactions but, to a large extent, also depends on a particular genetic background (Pembrey et al 2014).…”

“…Methylation of an rDNA promoter CpG site at position −133 relative to the transcriptional start site resulted in transcriptional silencing of the underlying rDNA copy and maternal LPD-defined low weaning weight in F1 was negatively correlated with hypomethylation of this site. Additionally, this outcome was specifically dependent on the presence of the A-allele from a neighboring C/A SNP at position −104 (Holland et al 2016). The study represents an example of an epiallele with transcriptional activity and resulting phenotypic consequences dependent on both early life exposure and genetics (Holland et al 2016).…”

“…F0 females were given a LPD until F1 offspring were weaned (Holland et al 2016). This dietary paradigm resulted in restricted growth in F1 mice, and RRBS analyses of the sperm methylome revealed the existence of a maternal LPD-induced DMR corresponding to repetitive ribosomal RNA-encoding genes (rDNA).…”

Regulation of growth: Epigenetic mechanisms?

“…Regarding non-imprinted genes, epigenetic alterations have notably been associated with genes involved in the metabolism (e.g. PPAR, RXRA) [11,12].…”