School of Biosciences

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. 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 human health.

What is the significance of gene dosage?

We are developing an allelic series spanning the IC2 domain (Figure 1) to study the consequences of loss of imprinting in normal developmental process and in disease. Using this approach, we have shown that Cdkn1c functions to directly restrict fetal growth (Figure 2) while Phlda2 restricts placental growth (Figure 3). We are currently investigating whether Cdkn1c and Phlda2 act synergistically to balance fetal growth with placental support. Poor in utero growth is linked to the development of type 2 diabetes and heart disease thus maintaining the correct balance of Phlda2 and Cdkn1c early in life will be important for adult health (Figure 4). 

Can the environment shape our epigenome influencing our susceptabilty to disease?

Epigenetic marks are flexible and may be influenced by lifestyle choices, particularly during very early life (Figure 5). We are exploring a variety of conditions to determine whether the genes within the domain we are studying respond to environmental cues and whether there are differences in the relative vulnerability of gametic verses somatic DMRs.

How and why are imprints maintained in the adult?

Establishing and maintaining the correct does of an imprinted gene is critical 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 also investigating the mechanisms for establishing and maintaining imprints.

Funding

Current live

BBSRC Project grant BB/G015465

Duration: 09/05/2009 to 08/05/2012

Title: Dissecting an epigenetic process that extrinsically governs fetal size

Funding: £336,118 (80% of £420,147)

Previous grants (Cardiff)

2009 Diabetes UK “Establishing pancreatic explants cultures as a technique to identify the very early developmental origins of type 2 diabetes

2006 Royal Society “Preliminary characterisation of histone modifications at the imprinted murine Neuronatin locus”

2005 DiabetesUK “Investigating glucose tolerance in a murine model of IUGR: A pilot study”

2005 Wellcome Trust “Analysing the phenotypic consequences of excess Cdkn1c, an imprinted cyclin-dependent kinase inhibitor, in mice”

2004 BBSRC Integrative Epigenetic Initiative PhD studentship “Investigation of the epigenetic events leading to heritable silencing of Cdkn1c”

Meetings

Annual Mammalian Genes, Development and Disease Meeting.

Next meeting July 2011, Bristol.

http://www.genetics.org.uk/page/3199/Sectional-Interest-Groups.html

http://www.cardiff.ac.uk/biosi/newsandevents/events/mgdd/index.html2011

Genetics Society Autumn Meeting: Phenotype and the flexible genome: the role of epigenetic processes in development and human disease

Friday 11 November 2011. The Royal Society, Carlton House Terrace, London

Collaborations

Professor Benjamin Tykco (USA)

Professor Mike Higgins (USA)

Professor Louis Lefebvre (Canada)

Dr Takahiro Arima (Japan)

Mr Richard Penketh (University Hospital of Wales)