Impacts of epigenomic drugs on female reproductive health

Epigenetics provides an interface between the environment and DNA function through the ability of epigenetic modifications to regulate gene expression. Environmental disruption of epigenetic programming is considered to underlie developmental origins of disease, a process by which early changes in development lead to life-long health consequences. 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 specialised function. Changes to this long-term memory are thought to underlie developmental origins of disease, but the epigenetic mechanisms involved are poorly understood. Epigenetic modifiers have been widely studied in some somatic tissues, but their roles in regulating ovarian folliculogenesis, female fertility and female endocrine state are poorly understood. The follicle encompasses the functional unit of the ovary and regulates endocrine homeostasis, leading to multiple influences, including on infertility, ovarian function and endocrine state. Impacts on ovarian function can compromise female reproductive health, including long term physiological impacts on fertility and endocrine state and consequences including increased incidence of bone, metabolic, heart and cardiovascular disease EED and EZH2 are essential components of the highly conserved epigenetic modifier, Polycomb Repressive Complex 2. PRC2 is also dysregulated in cancer, and drugs have been developed to target PRC2. However, these drugs act systemically, and their potential impacts on the ovary remain unknown. Recent work in our laboratory demonstrates that PRC2 plays essential roles in ovarian development. However, the role of PRC2 in regulating development of these organs and the consequences of epigenetically dysregulating function of PRC2 as a potential off-target impact of clinical treatment remain unknown, raising the possibility that measures that preserve fertility options and/ovarian function may be beneficial to patients. This project will use drugs that inhibit PRC2 function to treat ovarian tissue in culture to determine the potential for these drugs to have off-target impacts on folliculogenesis and/or ovarian function. A range of state of the art technologies, including immunofluorescence, advanced imaging, genome-wide sequencing, morphological and physiological, will be used to determine the impacts of PRC2 inhibiting drugs on ovarian cultures. The data obtained will reveal how epigenetic mechanisms regulate the ovarian function, providing insight into the epigenetic regulation of the ovary and processes regulating endocrine physiology. The project will address a critical knowledge gap in endocrinology and reproductive health by defining novel epigenetic processes that underpin ovarian function, aspects of which may be altered by lifestyle factors such as diet and drugs. Specifically, as PRC2 is commonly dysregulated in cancer (including ovarian cancer) and drugs targeting PRC2 have been developed for treatment, this work will also provide essential preclinical insights into the possible impacts of specific cancer therapies on endocrine state and whether patients should undergo fertility preservation.