School of Biosciences; Cardiff University
Genomic imprinting describes the parental-dependant monoallellic expression of some mammalian genes. Many of these genes are involved in regulating embryonic and extraembryonic growth and defective imprinting has a direct role in numerous human diseases. The competing effects on growth of oppositely imprinted genes has led to the proposal that there is an evolutionary 'tug of war" over access to maternal nutrients by the parental genomes.
Here we have used a bacterial artificial chromosome to generate biallelic expression of three imprinted genes, Cdkn1c, Phlda2 and Slcc22a18 (1,2,3). We observe embryonic and placental growth retardation supporting the parental conflict hypothesis but, more importantly, we demonstrate that two physically and mechanistically linked genes can act to control embryonic and extraembryonic growth independently. Furthermore, the placental insufficiency due to excess Phlda2 leads to late onset growth retardation with postnatal "catch-up", a growth profile observed in human IUGR individuals. The increased susceptibility of these individuals to diseases such as type II diabetes suggests that this imprinted gene, which is itself regulated by an epigenetic mechanism, may be involved in establishing an epigenetic profile in utero that has long term consequences for the development of human disease. (Support by The Wellcome Trust and Diabetes, UK)
John, RM, Ainscough, JF, Barton, SC, and Surani, MA. Distant cis-elements regulate imprinted expression of the mouse p57(Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith--Wiedemann syndrome. Hum Mol Genet 15: 1601-9, 2001.
Andrews, S, Wood, M, Barton, SC, Surani, MA, and John RM. Two physically and mechanistically-linked imprinted genes, Cdkn1c and Phlda2, act in parallel to regulate embryonic and extra-embryonic growth. (In preparation).
Salas, M, John, RM, Saxena, A, Barton, S, Frank, D, Fitzpatrick, G, Higgins, MJ, and Tycko B. Placental growth retardation due to loss of imprinting of Phlda2. Mech Dev. 121: 1199-210, 2004.