Achieving a successful pregnancy: Epigenetic regulation of fetal-maternal signaling

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

Pregnancy, which is experienced by over 700,000 women per year in the United Kingdom, is a dynamic, exquisitely coordinated process involving systemic and local changes in the mother to accommodate the metabolically demanding and immunogenic fetus. Disorders of human pregnancy, such as stillbirth, low birth weight, preterm birth and maternal diabetes may occur as a consequence of poor or inappropriate adaptation to pregnancy illustrating the importance of this highly regulated process, both for the health of the mother and for the well being of her children.

Many of the endocrine and metabolic changes that occur in the mother during pregnancy can be directly attributed to signals originating from the placenta. We are investigating the role of an imprinted gene in regulating these signals from the placenta to the mother. Imprinted genes, which are expressed in mammals from only one parental allele, play an important role in regulating embryonic growth and placental support.

In this study, we will use a model system in which we have engineered changes in the expression of the imprinted gene, Phlda2, in the placenta. Changing the amount of Phlda2 alters the composition of the placenta such that there is either decreased or increased expression of placental hormones that signal to the mother. Consequently mothers carrying these pups will be exposed to either too little or too much of these hormones during pregnancy. It is well known that in human pregnancies, abnormal levels of these hormones in maternal serum are associated with low birth weight and, in some case, fetal loss. Indeed, we observe both low birth weight and some evidence fetal loss when our mothers receive too little of the placental signals. In this proposal, we will simply ask whether mothers carrying pups with elevated expression or loss of expression of Phlda2 show indicators of abnormal adaptation to pregnancy.

What is remarkable about this study is that we will be able to show that an imprinted gene in the fetus can manipulate the mother's physiology during pregnancy. Additionally, we will provide data on the consequences of aberrant expression of Phlda2 on the health and well being of both the mother and her offspring.

Technical Summary

From very early in development, the mammalian embryo signals its presence to the mother in order to establish the pregnancy. Continued signaling throughout pregnancy ensures the healthy development of the fetus. Understanding how these signals are regulated is fundamental to our understanding of the processes required for a successful pregnancy.

Using mouse models we have shown that the imprinted Phlda2 gene encodes a negative regulator of a key signaling lineage of the mouse placenta, the spongiotrophoblast. Consequently mothers carrying pups in which Phlda2 expression is either elevated or ablated are exposed to either too low or too high signaling, respectively. We have found that mothers carrying these pups show changes in pancreatic gene expression. Furthermore, in our low placental signaling model both the transgenic and the non-transgenic pups, which share the same in utero environment, are low birth weight. These data suggest that mothers may fail to appropriately adapt to pregnancy as a consequence of altered Phlda2 expression in the placenta.

To obtain functional evidence for a role for Phlda2 in regulating the adaptation to pregnancy, we will examine fetal growth, fetal survival and time of delivery in our models of low and high placental signaling. We will obtain evidence that the alterations in fetal well being we observe occur as a consequence of inappropriate adaptations in the mother by examining maternal glucose homeostasis and by metabolic profiling of maternal serum. We will extend this study to identify other imprinted genes that act similarly within in the mouse placenta to regulate signaling lineages. In this way, we will demonstrate that genomic imprinting controls the maternal adaptations required for a successful pregnancy by regulating the placental cell types that induce these adaptations.

Planned Impact

Enhancing quality of life, health and well-being: Almost one tenth of the entire NHS budget, or about £9 billion a year, is spent managing low birth weight babies and their complications. Even where pregnancy is successful, the sub-optimal in utero environment experienced by the fetus may program diseases which manifest much later in life, such as type 2 diabetes, one of the biggest causes of mortality worldwide. Advancing our understanding of the underlying mechanisms that drive the normal adaptative processes of pregnancy in a model system has the potential to lead to improvements both in the short term and long term for a significant number of individuals in the UK and worldwide. Deregulated expression of Phlda2 as a consequence of a poor maternal diet may underlie some pregnancy complications as well as low birth weight and the later development of type 2 diabetes, something that could be addressed in Public Health strategies.

Livestock: Complications of pregnancy including prematurity, stillbirth and low birth weight are not solely a concern of human individuals. Our work may have some impact on the raising and breeding of domestic animals. For example, stillbirth or abortion in domestic animals is primarily due to infections, which can be managed by vaccination and good husbandry techniques, but a proportion of females abort or produce stillborn young with no infectious agent present.

The economy: Our discoveries have the potential to benefit the British economy by reducing costs to the NHS. The NHS is spending nearly 10% of its yearly budget treating pregnancy complications. A further 10% is spent on managing type 2 diabetes and obesity, which may occur as a consequence of a poor in utero environment. In addition to direct costs, there are also indirect costs to the economy associated with lost productivity.

Commercialisation: There is the potential for the development of biomarkers indicative of pregnancy complications. Biopsy of the placenta during pregnancy is not warranted except under extreme circumstances. However, our metabolic screen may identify potential biomarkers detectable in maternal blood indicative of abnormal Phlda2 expression.

Contributing towards evidence based policy-making and influencing public policies and legislation at a local, regional, national and international level: Gene-environment interactions - Phlda2 is known to be deregulated in response to a suboptimal in utero environment. We have genetically identified a causative role for Phlda2 in low birth weight in mice. Our current work suggests a link between fetal growth restriction, maternal health and the subsequent development of metabolic changes in a model organism. Our findings will stimulate studies to discover whether this holds true for human individuals. This may then lead to changes in the policies for the management of pregnant women.

Contributing to increasing public awareness and understanding of science, economic and societal issues: News media play a role in informing the way people understand science. The public understanding of issues such as climate change, stem cells and MMR have increased due to media coverage as a consequence of new discoveries reported in scientific journals. Similarly, public awareness of epigenetics and health will be increased by our work when published.

Enhancing the knowledge economy: Nothing is published linking Phlda2 to maternal health. Therefore the scientific discoveries we anticipate will provide new knowledge.

Worldwide scientific advancement to address issues of importance in other countries or globally: Studies on Phlda2 may provide a tool to address maternal health worldwide .

Delivering and training highly skilled researchers: This work will provide training in techniques related to placental biology and in vivo studies of maternal physiology increasing the pool of trained technical experts in the UK with this sought after expertise.
 
Description This grant has now finished. We acheived the key aims as listed in our milestones. We have shown that elevated expression of an imprinted gene called PHLDA2 causes asymmetrical growth restriction in mice (AIM1, two publications). We have found other imprinted genes that behave in a similar way to PHLDA2 (Aim 3, one publication). We have shown that dam's carrying fetuses mutant for PHLDA2 have an abnormal metabolism in pregnancy as hypothesised (AIM2, in preparation). This work investigation a fundamental mechanism whereby the fetus signal via the placenta to the mother is critically important for healthy life as poor growth in utero is linked to adverse outcomes for offspring. Importantly, the work has great translational relevance for humans as low birth weight is a major complication affecting 7.2% of live births every year in the UK. Our work highlights a novel mechanism underlying low birth weight and, moreover, indicates that mothers of low birth weight babies may be at risk of other pregnancy complications and that these co-occurances arise from defects in placental development. Further impact from this work: SJT has now obtained a prestigious fellowship at Cambridge University, we were successful in obtaining two RC grants based on our findings from this study one of which is translating our finding in a mouse model to human pregnancy. We also have two PhD students whose project come from this study.
Exploitation Route Our findings have led to a new direction for our research program. We have had two grant applications funded for further work - one from the MRC to translate our findings into human pregnancy and one from BBSRC to continue with fundamental research examining the mechanisms linking maternal diet to placental endocrine dysfunction and maternal care deficits.
Sectors Healthcare

 
Description Research led to an exploration of findings in human cohorts. This led to a) MRC grant funding, b) engagement with healthcare workers, c) Public engagement
First Year Of Impact 2011
Sector Healthcare
Impact Types Cultural,Societal

 
Description Neuroscience and Mental Health Board
Amount £900,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 03/2015 
End 03/2018
 
Description Maternal mood disorders, childhood wellbeing and Placental gene expression network 
Organisation Health and Care Research Wales
Country United Kingdom 
Sector Public 
PI Contribution NISCHR CYPRN finding a networking event to bring together individuals involved in both clinical and basic research to explore the initiation of a Wales/South West of England research program to investigate maternal mood disorders, childhood mental health and placental gene expression.
Collaborator Contribution Funding for the meeting
Impact Funding of research (MRC)
Start Year 2013
 
Description 2013 Maternal mood disorders, childhood wellbeing and placental gene expression network meeting, Cardiff 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Discussed grant proposal

Submitted grant proposal
Year(s) Of Engagement Activity 2013
 
Description Engagement with trainee midwives 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact We present two 3 hr workshops for Year 1 and year 3 trainee midwives on maternal lifestyles and low birth weight (Year 1) and maternal mood disorder in pregnancy (Year 3).
Year(s) Of Engagement Activity 2015
 
Description Engaging with public 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Stimulated questions from children and adults

Request for future activity
Year(s) Of Engagement Activity 2013
 
Description Engaging with public 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sparked discussion with children and parents

Request for future activity
Year(s) Of Engagement Activity 2014
 
Description Galton Institute Genetics Update day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Presentation on Epigenetics as part of a Galton Institute Genetics Update day for A-level Biology
Year(s) Of Engagement Activity 2015
 
Description Presentation to healthcare professionals 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Engagement of midwives and clinicians in discussion

Midwives expressed interest in supporting academic research
Year(s) Of Engagement Activity 2013
 
Description Presentation to healthcare professionals 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Sparked questions and discussion with midwives and clinician.

Clinician involvement in supporting research
Year(s) Of Engagement Activity 2012
 
Description Presentation to healthcare professionals 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Sparked questions and discussions

Interest from clinicians and midwives in supporting research
Year(s) Of Engagement Activity 2011
 
Description School outreach 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk sparked questions and discussions. Talk was to teachers who then requested school visits

School visits requested but we did not have the personal to deliver
Year(s) Of Engagement Activity 2013
URL http://sites.cardiff.ac.uk/curriculumsupport/academic-school/college-of-biomedical-life-sciences/bio...
 
Description Science Week "healthy lifestyles in pregnancy" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We present a workshop as part of "Biology Rocks" at National Museum of Wales. Open to public.
Year(s) Of Engagement Activity 2015
URL http://www.museumwales.ac.uk/blog/2015-10-13/Biology-Rocks-at-National-Museum-Cardiff/