Team Laurent JOURNOT

Parental genomic imprinting is an epigenetic mechanism of gene regulation that restrains the expression of a gene to one allele depending on its parental origin. Genomic imprinting is essential for mammalian development. It targets ~150 genes in placental mammals (eutherians) and less than a dozen in marsupials (metatherians); it does not affect egg-laying mammals (prototherians) and other clades (birds, reptiles, amphibians, fishes…).

The mechanisms that account for the mono-allelic, parent-of-origin-dependent expression of imprinted genes have been studied in details (Hanna & Kelsey, Heredity (Edinb), 2014; Ferguson-Smith, Nat Rev Genet, 2011). A large number of imprinted genes cluster at a limited number of imprinted loci. The repression of one of their parental alleles is controlled by the so-called Imprinting Control Regions (ICRs), which usually comprise a Differentially Methylated Region (DMR). The (de)methylation of the paternal and maternal DMRs governs the expression/repression of the neighboring imprinted genes.

Imprinting defects at defined loci result in different syndromes with complex phenotypes: Silver-Russel, Angelman, Prader-Willi, Beckwith-Wiedemann and TNDM (Transient Neonatal Diabetes Mellitus). In addition, a number of imprinted genes are involved in tumour formation as oncogenes or tumour suppressor genes.

We showed that imprinted genes belong to a network of co-regulated genes we named the imprinted gene network (IGN) (Varrault et al., Dev. Cell, 2006). We next found that the IGN is regulated at the transition from proliferation to quiescence and differentiation during fibroblast cell cycle withdrawal, adipogenesis in vitro, and muscle regeneration in vivo. The IGN also includes bi-allelically expressed genes, notably genes controlling the composition of the extracellular matrix. Our observations suggest that imprinted genes are involved in a common biological process that may account for their seemingly diverse roles in embryonic development, obesity, diabetes, muscle physiology, and neoplasm (Al Adhami et al., Genome Res., 2015).

Nestin-positive neural progenitors (green) generated from uniparental mouse embryonic stem cells expressing the cortical marker Pax6 (red) and stained with DAPI (blue).