Dissecting an epigenetic process that extrinsically govern fetal size

在哺乳动物中，胚胎生长是微调的，胎盘为最佳的胚胎生长提供了足够的支持。太少的支持将产生不利的影响，因为胚胎的生长受到抑制，这可能导致宫内生长受限。太多的支持是浪费的，而且会不必要地消耗母亲的资源。因此，胎儿和支持结构的协调工作至关重要。印记基因在哺乳动物中只表达一种亲本等位基因，在这一过程中发挥着关键作用。我们正在研究一组印记基因，它们位于一个离散的染色体区域内，由一个印记中心调控。这些基因表达的任何全球变化都会对胚胎发育和胎盘生长产生灾难性的后果。我们已经确定这些基因中的一个，CDKN1c，是该区域内胚胎生长的主要调节因子。其他几个基因在胎盘中表达，其中一些已被证明在胎盘发育中发挥关键作用。在这项提案中，我们将确定其中两个基因，即Phlda2和Slc22a18，是否与CDKN1c协同作用，平衡胚胎生长和胎盘功能。这项工作对于我们理解胎盘如何发挥最佳健康功能非常重要。有趣的是，我们正在研究的基因在基因组中是相邻的，通过研究它们，我们可能会更多地了解印记这些基因的功能后果，以及这可能如何影响哺乳动物胎盘的进化。关键的是，我们还将更多地了解这些基因表达放松对发育和疾病的影响。

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.