Does abnormal one-carbon metabolism or hyperglycaemia in utero cause epigenetic change and fetal programming of cardiome
Lead Research Organisation:
Queen Mary University of London
Department Name: Blizard Institute of Cell and Molecular
Abstract
Diabetes and cardiovascular disease (the ‘cardiometabolic‘ diseases) are becoming increasingly common throughout the world. The risk of developing these diseases relates to both genetic inheritance and a person‘s environment. The effects of environment are particularly important during pregnancy, and studies of malnourished and diabetic mothers show an increased risk of cardiometabolic disease in their children. This idea of disease being ‘programmed‘ during fetal development has been studied across populations and in animal experiments, but the mechanisms through which it occurs are not understood.
In this respect, the field of epigenetics is providing an exciting insight into how this programming might occur. It describes how environmental triggers can affect how genes are switched on or off via a sequence of chemical reactions around the structure of DNA. This study will look at how high blood glucose levels and poor nutrition in mothers could cause epigenetic changes that put offspring at risk of cardiometabolic disease. The study will be done in mice as well as humans to identify whether these changes can be inherited through generations. New techniques involving both laboratory experiments and computerised mathematical analysis will be used to answer these questions.
In this respect, the field of epigenetics is providing an exciting insight into how this programming might occur. It describes how environmental triggers can affect how genes are switched on or off via a sequence of chemical reactions around the structure of DNA. This study will look at how high blood glucose levels and poor nutrition in mothers could cause epigenetic changes that put offspring at risk of cardiometabolic disease. The study will be done in mice as well as humans to identify whether these changes can be inherited through generations. New techniques involving both laboratory experiments and computerised mathematical analysis will be used to answer these questions.
Technical Summary
Aims and objectives: to understand the epigenetic basis of fetal programming of type 2 diabetes and cardiovascular disease. The study will look at two environmental insults in utero for which there is epidemiological and early experimental evidence to support a role in epigenetic-mediated disease pathogenesis. The study also seeks to study the transgenerational effects of this epigenetic change through both somatic tissues and the germline.
Design and methodology: A human model will identify individuals with gestational diabetes and hyperhomocysteinaemia from a local population at high risk of cardiometabolic disease. DNA from offspring cord blood will be studied and compared to parental DNA to examine de novo environmental effects on DNA methylation. A rodent model of gestational diabetes and methionine-induced hyperhomocysteinaemia will mirror this model, allowing investigation epigenetic variants and their inheritance between successive generations using sperm and oocytes and controlled breeding. In both models, epigenetic will be identified in offspring by the use of ‘next generation‘ sequencing (Solexa) and custom bioinformatic analysis. This will be followed by targeted bisulphite sequencing of familial epialleles of interest. Further study will examine tissue-specific epigenetic variants, RNA expression and chromatin remodelling.
Scientific and medical opportunities: The design of this study and techniques used will provide understanding of environmentally-mediated epigenetic reprogramming and inheritance from a truly genome-wide perspective. Identification of common dietary and metabolic insults in pregnancy that may predispose to disease risk in offspring will allow effective treatment interventions against a cluster of conditions that is increasing in prevalence globally.
Design and methodology: A human model will identify individuals with gestational diabetes and hyperhomocysteinaemia from a local population at high risk of cardiometabolic disease. DNA from offspring cord blood will be studied and compared to parental DNA to examine de novo environmental effects on DNA methylation. A rodent model of gestational diabetes and methionine-induced hyperhomocysteinaemia will mirror this model, allowing investigation epigenetic variants and their inheritance between successive generations using sperm and oocytes and controlled breeding. In both models, epigenetic will be identified in offspring by the use of ‘next generation‘ sequencing (Solexa) and custom bioinformatic analysis. This will be followed by targeted bisulphite sequencing of familial epialleles of interest. Further study will examine tissue-specific epigenetic variants, RNA expression and chromatin remodelling.
Scientific and medical opportunities: The design of this study and techniques used will provide understanding of environmentally-mediated epigenetic reprogramming and inheritance from a truly genome-wide perspective. Identification of common dietary and metabolic insults in pregnancy that may predispose to disease risk in offspring will allow effective treatment interventions against a cluster of conditions that is increasing in prevalence globally.
