Defining the epigenetic origins of maternally inherited disease.

The notion that non-genetic factors in oocytes (eggs) and sperm can alter development and postnatal health in offspring is gaining traction with our increased understanding of epigenetic programming in male and female germ cells. Epigenetics provides an interface between the environment and DNA function through the ability of epigenetic modifications to regulate gene expression. Primary epigenetic modifications involve methylation of the DNA or chemical modifications, such as methylation, acetylation, phosphorylation, of the histones that facilitate DNA organisation and packaging. These modifications regulate the combination of genes that are switched on or off in a cell, and can provide a “long-term memory” of the transcriptional state for that cell and its progeny, substantially contributing to the maintenance of the cell’s specialized function. Epigenetic modifiers have been widely studied in somatic tissues, but their roles in the germline are poorly understood. Germ cells are unique in that they undergo the most extensive epigenetic reprogramming of any in vivo cell type, a process that ultimately results in establishment of specialized epigenetic information in oocytes and sperm. Some of this information is transmitted via the oocyte and sperm to the next generation, and disruption of this inherited epigenetic information can lead to developmental defects and disease in offspring The Germ Cell Development and Epigenetics group aims to understand how epigenetic modifiers acting in germ cells, alter development and health in offspring. One such modifier is EED which establishes methylation on lysine 27 in histone 3 (H3K27me3), thereby repressing gene expression (turning genes off) in animal cells, including in humans. To understand the role of EED in epigenetic programming of oocytes and in inheritance, we developed a model for deleting Eed only from growing oocytes in mice. This model provides a unique opportunity to study epigenetic inheritance in genetically identical offspring in the absence of maternally contributed confounding factors. Our studies demonstrate that EED-mediated epigenetic programming in oocytes is important for offspring development, but the mechanisms remain unclear. This project will examine: (i) how the loss of EED activity impacts on epigenetic programming in oocytes, and (ii) how EED-mediated programming in oocytes affects development and postnatal health in offspring. (iii) how altered fetal and placental development in offspring affects the mother's physiology This research will involve application of genome-wide sequencing, immunofluorescence and confocal imaging and a range of molecular and cell biological approaches. Determining how epigenetic programming in oocytes and sperm regulates outcomes offspring is highly topical and of direct relevance to understanding the impacts of environmental impacts, such as drugs, diet and toxins, on health and developmental outcomes in humans.