Dissecting an epigenetic process that extrinsically govern fetal size

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In mammals, embryonic growth is finely tuned and the placenta provides sufficient support for optimal embryonic growth. Too little support will have an adverse effect as embryonic growth is restrained which can result in intrauterine growth restriction. Too much support is wasteful and uses up maternal resources needlessly. It is therefore critical that the fetus and the supporting structures are working in harmony. Imprinted genes, which are expressed in mammals from only one parental allele, play a key role in this process. We are investigating a group of imprinted genes that are located within a discrete chromosomal region that is regulated by a single imprinting centre. Any global change in the expression of these genes has catastrophic consequences on both embryonic development and placental growth. We have already identified one of these genes, Cdkn1c, as the major regulator of embryonic growth within this domain. Several other genes are expressed in the placenta and some have been shown to play a critical role in placental development. In this proposal, we will determine whether two of these genes, known as Phlda2 and Slc22a18, act synergistically with Cdkn1c to balance embryonic growth and placental function. This work is important in our understanding how the placenta functions for optimal health. Intriguingly, the genes we are working on are adjacent in the genome and by studying them we may learn more about the functional consequences of imprinting these genes and how this may have influenced the evolution of the mammalian placenta. Critically, we will also learn more about the consequences of deregulated expression of these genes on development and disease.