Defining how high fat diet and epigenetic factors interact to modulate metabolic disease inheritance

Project description

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 chromatin (DNA + associated histone proteins) organisation and gene expression. Epigenetic modifications regulate the combination of genes that are switched on or off in a cell, and are heritable through cell divisions, meaning that they can provide a “long-term memory” that stabilises cell function and maintains cell identity.

Epigenetic modifiers have been widely studied in somatic tissues, but their roles in the germline (eggs and sperm) are understood in less detail. It is clear that specific environmental conditions may disrupt epigenetic information established in eggs and sperm and this can lead to developmental defects and disease in offspring. However, epigenetic mechanisms do not act in isolation, but interact with both genetic and environmental conditions present in an individual.

For example, an individual who has a genetic change that compromises epigenetic modifier gene function may be more severely impacted by a specific environmental challenge than an individual with “normal” epigenetic gene function. Such environmental challenges may exacerbate impacts on the egg or sperm epigenome, and thereby more severely affect offspring development and health.

We have recently demonstrated that the key epigenetic modifier EED regulates epigenetic programming of oocytes and in inheritance in offspring in mice (Prokopuk et. al. Clinical Epigenetics 2018; Jarred et.al. 2022 Clinical Epigenetics; Oberin and Petautschnig et. al. 2024 eLife). This alters fat and muscle content in genetically identical offspring in the absence of maternally contributed confounding factors (Prokopuk et. al., Clinical Epigenetics 2018), indicating that metabolic parameters may be altered in these mice.

High fat diet and obesity represent common environmental challenges in Australia and other societies globally. This project aims to determine how environmental impacts mediated by high fat diet interact with EED-mediated epigenetic programming in growing oocytes.

Hypothesis: 1. High fat diet will exacerbate the impacts of depleting EED-dependent epigenetic programming in oocytes; 2. High fat diet will exacerbate metabolic disease in offspring derived from oocytes that lack EED-dependent epigenetic programming.

Aim 1: Determine how high fat diet affects germline epigenetic programming in female mice that have normal or compromised EED function during oocyte growth.

Aim 2: Determine how high fat diet affects metabolic outcomes in offspring derived from eggs that maintained or lacked EED-dependent epigenetic programming during oocyte growth.

Determining how environmental challenges such as drugs, diet and toxin interact with compromised epigenetic programming in oocytes and sperm to regulate offspring outcomes is highly topical and directly relevant to understanding human health and disease.

This research will involve application of genome-wide sequencing, immunofluorescence and confocal imaging and a range of molecular and cell biological approaches.