Dr Rosalind John - PhD
How Epigenetic Marks direct Mammalian Development and drive Human Disease
Genomic imprinting is an epigenetic system, first initiated in the germline, that directs the allele-specific expression of a small set of developmentally important genes (Figure 1). The goal of our research is to develop an understanding of the dosage-related function of imprinted genes firstly, to provide an explanation for the driving force for imprinting and, secondly, to determine the importance of maintaining the correct dose of an imprinted gene for optimum health.
Figure 1: Genomic imprinting describes the monoallelic, parent-of-origin specific expression of genes
What is the significance of gene dosage?
We are developing an allelic series spanning the IC2 imprinted domain on mouse distal chromosome 7, syntenic with the Beckwith-Wiedemann Syndrome/Silver Russell Syndrome region on human chromosome region 11p15, to study the consequences of loss of imprinting in normal developmental processes, and in disease (Figure 1). Using this approach, we have shown that several genes within this domain play a key role in regulating placental development converging on the endocrine lineages of the placenta (Figure 2). Additionally, we have shown that loss of imprinting of Cdkn1c intrinsically restricts fetal growth (Andrews et al., 2007) while loss of expression results in fetal overgrowth (Tunster, 2011). In contrast, the imprinted Phlda2 gene acts to extrinsically restrict late fetal growth (Tunster et al., 2010) with consequences for later life health. Most recently we are applying BAC technologies to study the imprinted Ascl2 gene. Our work highlights the importance of controlling the dosage of imprinted genes in placental development and fetal growth.
Figure 2: Imprinted genes regulate placental development
Epigenetic programming of maternal adaptations to pregnancy
The placenta is not simple transportations device but an endocrine organ flooding the maternal system with hormones and cytokines to induce the changes in the mother necessary to sustain a healthy pregnancy. Since the imprinted genes we are studying regulate the placental endocrine lineages, aberrant expression of these genes may have a consequence for maternal wellbeing. We our currently using our model to investigate this hypothesis funded by BBSRC grant “Achieving a successful pregnancy: Epigenetic regulation of fetal-maternal signaling”.
Figure 3: Do imprinted genes regulate maternal adaptations during pregnancy?
Since the imprinted genes we are studying regulate placental development, fetal growth and, very likely, maternal adaptations to pregnancy, their aberrant expression may play a role in human disorders of pregnancy including low birth weight, gestational diabetes and still birth. By integrating the knowledge gained from our models with studies on human samples, our work will promote the optimal interpretation of clinical data with a longer term goal of improving diagnostic performance and the identification of possible therapeutic targets for treatment.
Study Title: “Determining the expression levels of a set of imprinted genes in the term placenta from both normal and atypical pregnancies”
Chief Investigator: Mr Richard J A Penketh (Cardiff and Vale University Health Board)
REC number: 10/WSE02/10 R&D number: 09/RPM/4669
UK Clinical Research Network Study Portfolio http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=12675
How and why are imprints maintained in the adult?
Establishing and maintaining the correct does of an imprinted gene is essential for normal development and adult health. Gametic imprints are established in the germline and act to set up domains of imprinted gene expression. Somatic imprints, which are established after the initiation of imprinted expression, serve to “lock-down” imprinted expression for the lifespan of the organism. We are investigating the mechanisms for establishing and maintaining imprints, and identifying environmental factors that influence these epigenetic processes.
20012-2015 BBSRC Project grant BB/J015156/1
Title: Achieving a successful pregnancy: Epigenetic regulation of fetal-maternal signaling
Next meeting July 2013, Cardifff.
- Professor Ben Tycko (Columbia, USA).
- Professor Michael Higgins (USA).
- Dr Takahiro Arima (Sendai, Japan).
- Professor Louis Lefebvre (UBC, Canada).
- Dr Mark Christian, Imperial College
- Professor Toni Vidal-Puig, Cambridge University
- Mr Richard Penketh, Cardiff & Vale NHS Trust