Dr Michelle Holland, Blizard Institute, Barts and The London School of Medicine and Dentistry
MRC INTEGRATIVE EPIDEMIOLOGY UNIT (IEU)
Thursday, 12th January, 2017
16.00 – 17.00 - Room OS6 – Oakfield House
Dr Michelle Holland
Barts and The London School of Medicine and Dentistry
rDNA as a Target of Nutritional Programming
Early life nutrition can influence development and life-time health, a phenomenon termed ‘developmental programming.’ We have very recently reported the effect of maternal protein restriction on offspring outcomes at both the level of phenotype and the epigenome in a mouse model (Holland et al, 2016, Science). Intriguingly, we identified DNA methylation differences at a single region, localised to rDNA. rDNA is a non-coding repetitive element excluded from genomic assemblies. It codes for RNA components of ribosomes. Further examination revealed that intra-genomic copies of rDNA show sequence divergence, even in inbred mice and that only specific genetic variants show an epigenetic response to early life nutrition. Furthermore, the magnitude of the epigenetic response correlates with diet induced phenotypes. Our work highlights that interactions between genetics-epigenetics and phenotype in this example are ‘cryptic,’ only emerging after exposure to an environmental insult. Furthermore, these effects are observed at a functional non-coding genomic region that is frequently overlooked in the context of genome-wide gene-environment interactions.
Michelle’s research interests include the molecular basis of gene environment interactions in mammals, especially in the context of developmental programming and transgenerational effects. Her recent work has identified ribosomal DNA, a repetitive genomic element that encodes the RNA components of ribosomes as a region in which underlying genetic variation interacts with the early nutritional environment to induce an epigenetic response that persists throughout the life course. Michelle wishes to build upon this work by undertaking mechanistic studies to establish the consequences of these effects on protein translation and ultimately, phenotype, with a view to enhancing our understanding of how such effects might contribute to complex human diseases.