Mechanisms of epigenetic inheritance
Supervisor:Dr. Erica Watson
Second Supervisors DepartmentWellcome Trust Sanger Institute
Transgenerational epigenetic inheritance occurs when an environmental stressor (e.g., vitamin deficiency) influences epigenetic patterns leading to developmental phenotypes and/or disease. Remarkably, these pathologies can be inherited by subsequent generations even in the absence of the stressor. The mechanism by which this occurs is not well understood, but excludes changes to the DNA base sequence and is thought to involve epigenetic mechanisms including DNA methylation, histone modifications and small non-coding RNA. The goal of our research is to explore the mechanism of transgenerational epigenetic inheritance in a genetic mouse model of abnormal folate metabolism that displays multigenerational inheritance of developmental phenotypes (Padmanabhan et al, 2013 Cell). Folate (also known as folic acid) is a vitamin that is required by one-carbon metabolism for cellular methylation reactions (e.g., methylation of DNA, histones, RNA). Using our model, potential projects will focus on assessing the germline and embryo for the disruption of chromatin and small non-coding RNA expression that might directly lead to neural tube, heart and placental defects in these individuals and/or in their eventual offspring. Techniques used will be next generation sequencing and bioinformatic analysis (a bioinformatician is also on hand), germ cell collection, embryo dissection and phenotyping, embryo manipulation or injection and uterine transfer, and molecular and epigenetic analysis.
Our research in mice indicates that folate deficiency in an individual might affect the development and health of their children, grandchildren and great grandchildren even if they have a normal diet themselves. The next step will be to verify the multigenerational effect we observe in folate-deficient humans. We are working towards finding a suitable patient group. Understanding the epigenetic mechanism of transgenerational inheritance will have implications for preventative medicine and give further sound evidence in support of government programmes of folate-fortification of food, the implementation of which are currently under consideration in the UK. Furthermore, our mechanistic findings can be applied to the multigenerational effects of other non-communicable diseases, such as diabetes and obesity, in hopes of stemming their high frequency in the UK population and elsewhere.