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An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming


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Publication Date: 
12/04/2012
Authors: 
Radford EJ, Isganaitis E, Jimenez-Chillaron J, Schroeder J, Molla M, Andrews S, Didier N, Charalambous M, McEwen K, Marazzi G, Sassoon D, Patti ME, Ferguson-Smith AC.
Citation: 
PLoS Genet. 2012 Apr;8(4):e1002605. Epub 2012 Apr 12.
DOI: 
10.1371/journal.pgen.1002605
Abstract
Environmental factors during early life are critical for the later metabolic
      health of the individual and of future progeny. In our obesogenic environment, it
      is of great socioeconomic importance to investigate the mechanisms that
      contribute to the risk of metabolic ill health. Imprinted genes, a class of
      functionally mono-allelic genes critical for early growth and metabolic axis
      development, have been proposed to be uniquely susceptible to environmental
      change. Furthermore, it has also been suggested that perturbation of the
      epigenetic reprogramming of imprinting control regions (ICRs) may play a role in 
      phenotypic heritability following early life insults. Alternatively, the presence
      of multiple layers of epigenetic regulation may in fact protect imprinted genes
      from such perturbation. Unbiased investigation of these alternative hypotheses
      requires assessment of imprinted gene expression in the context of the response
      of the whole transcriptome to environmental assault. We therefore analyse the
      role of imprinted genes in multiple tissues in two affected generations of an
      established murine model of the developmental origins of health and disease using
      microarrays and quantitative RT-PCR. We demonstrate that, despite the functional 
      mono-allelicism of imprinted genes and their unique mechanisms of epigenetic
      dosage control, imprinted genes as a class are neither more susceptible nor
      protected from expression perturbation induced by maternal undernutrition in
      either the F1 or the F2 generation compared to other genes. Nor do we find any
      evidence that the epigenetic reprogramming of ICRs in the germline is susceptible
      to nutritional restriction. However, we propose that those imprinted genes that
      are affected may play important roles in the foetal response to undernutrition
      and potentially its long-term sequelae. We suggest that recently described
      instances of dosage regulation by relaxation of imprinting are rare and likely to
      be highly regulated.