DMMC Course: EPIGENETICS: FROM MECHANISMS TO MEDICINES

1140-1230 Monday 25 June 2007. O’Reilly Hall, University College Dublin.

Maternally expressed microRNAs as trans-regulator at the callipyge locus?
Dr Carole Charlier (University of Liège, Belgium)

The callipyge mutation (CLPG) is responsible of a muscular hypertrophy phenotype in sheep. The particularity of this phenotype is its mode of inheritance, called polar overdominance, where only the paternal heterozygous individuals exhibit the trait. It has been mapped to the one megabase DLK1-GTL2 imprinted domain, and identified as an A to G transition in an intergenic region, 32kb 5’ from the GTL2 gene. It is part of an evolutionary conserved cis-long range control element supposed to be needed for the post-natal repression of the central core genes in skeletal muscle (review by Georges et al., 2004).
We have demonstrated that the CLPG mutation alters the muscular epigenotype of the DLK1-GTL2 intergenic region in cis, altogether leading to a post-natal ectopic expression of the regulated genes in this tissue (Takeda et al., 2006). The muscular hypertrophy phenotype is due to the lack of repression of paternally expressed genes (DLK1 and/or PEG11) (Davis et al., 2004). The observed polar overdominance phenomenon would be the result of a trans-inhibition of the paternally expressed genes mediated by the maternally expressed microRNA (Davis et al., 2005). An additional layer of complexity has been recently added as we have shown that a subset of miRNAs from the domain are edited in skeletal muscle of sheep (Caiment et al., in preparation).
What could be the evolutionary meaning of all this? Both DLK1 and PEG11 seem to be involved in placental and foetal growth. Hence, it is possible that the evolutionary forces at the heart of the parental conflict hypothesis have recruited madumnal miRNAs to counteract padumnal growth enhancers.