The long-term goal of this project is to identify the molecular components underlying the heritability of ethanol's effect on germ cells. Germ cells are the bridge between generations and their integrity is paramount to the health and viability of all organisms. As such, the dysregulation of germ cells function significantly contributes to infertility and is also the leading cause of birth defects and infant deaths in the United States. Remarkably, although there is a clear contribution of ethanol to the etiology of human germ cell errors, its mechanisms of action, especially at embryonic stages of germ cell differentiation, have remained elusive. One largely under-explored area of ethanol's effect is the perturbation of germ cells' epigenome. This is particularly significant as (1) ethanol has been shown to strongly impact the epigenome of diverse somatic cell types and (2) embryonic germ cells are vulnerable to epigenetic-modifiers as they undergo an extensive remodeling of their chromatin which includes genome-wide demethylation and the establishment of a complex pattern of histone modifications. The failure to properly regulate these histone marks leads to spurious repetitive element expression, germ cell death and infertility. Furthermore, preliminary evidence gathered in the powerful genetic model system C. elegans indicates that exposure to ethanol leads to a heritable desilencing of normally repressed chromatin in germ cells. Here, we propose to leverage two complementary germ cell models, the nematode C. elegans and in vitro generated mouse germ cells, to elucidate the molecular nature of ethanol's epigenetic alterations. We will achieve this goal by first demonstrating the sensitivity of germ cells to physiological ethanol concentrations elicited from direct or ancestral exposure. We will then thoroughly characterize the epimutations arising from ethanol exposure on stem cell- derived mouse primordial germ cells at the time of their epigenetic remodeling. We expect this research to provide a much-needed comprehensive examination of the epigenetic changed that are correlated with a particular sensitivity of early germ cells to ethanol.
Germ cells, which are the only cells that are passed on from generation to generation, are exquisitely sensitive to environmental insults. Here, we propose to investigate the effect of alcohol exposure on the epigenome of germ cells and investigate its consequence on reproduction over multiple generations. This work will be particularly important in revealing novel aspects of alcohol-induced reproductive health deficits.
| Camacho, Jessica; Truong, Lisa; Kurt, Zeyneb et al. (2018) The Memory of Environmental Chemical Exposure in C. elegans Is Dependent on the Jumonji Demethylases jmjd-2 and jmjd-3/utx-1. Cell Rep 23:2392-2404 |
| Weinhouse, Caren; Truong, Lisa; Meyer, Joel N et al. (2018) Caenorhabditis elegans as an emerging model system in environmental epigenetics. Environ Mol Mutagen 59:560-575 |
