Regulation of ribosomal RNA expression across the lifespan is fine-tuned by maternal diet before implantation

Oleg Denisenko,Emma S Lucas,Congshan Sun,Adam J Watkins,Daniel Mar,Karol Bomsztyk,Tom P Fleming

doi:10.1016/j.bbagrm.2016.04.001

Abstract

Cells and organisms respond to nutrient deprivation by decreasing global rates of transcription, translation and DNA replication. To what extent such changes can be reversed is largely unknown. We examined the effect of maternal dietary restriction on RNA synthesis in the offspring. Low protein diet fed either throughout gestation or for the preimplantation period alone reduced cellular RNA content across fetal somatic tissues during challenge and increased it beyond controls in fetal and adult tissues after challenge release. Changes in transcription of ribosomal RNA, the major component of cellular RNA, were responsible for this phenotype as evidenced by matching alterations in RNA polymerase I density and DNA methylation at ribosomal DNA loci. Cellular levels of the ribosomal transcription factor Rrn3 mirrored the rRNA expression pattern. In cell culture experiments, Rrn3 overexpression reduced rDNA methylation and increased rRNA expression; the converse occurred after inhibition of Rrn3 activity. These observations define novel mechanism where poor nutrition before implantation irreversibly alters basal rates of rRNA transcription thereafter in a process mediated by rDNA methylation and Rrn3 factor.

Highlights

Nutrient availability is one of the factors that limit rates of cell transcription, growth and division
In 17 dpc fetal samples, the level of rDNA methylation was increased in LPD but not Emb-LPD compared to NPD animals (Fig. 3A)
These observations indicate that cellular RNA content and rDNA methylation are linked in animal tissues and that transcription changes associated with rDNA methylation at least in part account for changes in per cell RNA content induced by maternal diet

Summary

Introduction

Nutrient availability is one of the factors that limit rates of cell transcription, growth and division. Extensive studies in animal models and epidemiological evidence from across world populations have demonstrated that early environment, poor nutrition in utero, is a risk factor for chronic diseases in adulthood [1,2], indicating that permanent changes in transcription might be involved. A common phenotype in these studies is the combination of low birth weight (LBW, an index of poor fetal growth) with excessive ‘catch-up’ growth during early postnatal life. Poor maternal conditions would cause fetal adaptations to restrict growth and conserve energy for developmental needs. These responses would become maladaptive if nutrient levels improved postnatally leading to excess growth, nutrient storage and later disease [3,4]. “thrifty genes” [5] common to different species were not found and the “thrifty phenotype” framework remains hypothetical

Methods

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Discussion

Conclusion