Epigenetic Reprogramming in a Dish - an in vitro Model of Transgenerational Epigenetic Inheritance

It is now well established that parental lifestyles or experiences, environmental conditions, and/or exposures can alter the epigenome to cause epimutations which manifest as changes in DNA methylation, histone modification patterns, and/or chromatin structure in animal models or humans. Epimutations can predispose disease states that can be transmitted to descendants in subsequent generations through inter- or transgenerational epigenetic inheritance. Previous studies have shown that exposure to environmental agents known as endocrine disruptor chemicals (EDCs) can alter the epigenome causing epimutations. However, despite in vivo studies of the induction of epimutations by many different EDCs, there remain multiple unanswered questions including whether there are cell-type specific differences in susceptibility to EDC-induced epimutagenesis, whether this may be related to cell-type specific differential expression of relevant endocrine receptors, and whether or not EDC-induced epimutations are impacted by epigenetic reprogramming associated with normal transitions in cell fate. We propose a project designed to address these gaps in knowledge utilizing in vitro methodologies, that will facilitate high -resolution/-throughput studies at the cellular and molecular levels in a rapid and cost-efficient manner, minimizing the need for live animal studies. We found that there was indeed a difference in cell type-specific differences in EDC-induced epimutagenesis and this susceptibility correlated with presence or absence of relevant endocrine receptors. Finally, we saw that induced epimutations led to a certain prevalence of disruption to gene expression and DNA methylation to persist through cell state transitions. These results may set the stage for more in-depth studies into the underlying mechanism regulating EDC-induced epimutagenesis.