Germline-mediated Transgenerational Epigenetic Inheritance of Paternal Epimutations Induced by a High Fat Diet
It is focused on investigating mechanisms underlying the sequential series of events that includes transmission of epimutations from the HFD/-Ex F0 sperm to F1 fetus to F1 immature pup to F1 adult to induction of epigenetic disease in F1 offspring. With its overall comprehensive scope, as well as its potential to very productively integrate with Projects 1 & 2, Project 3 will represent an in-depth study, the comprehensive nature of which is unparalleled in the field.
Project Leader
Dr. John R. McCarrey
Significance
The research proposed here is significant because it is designed to 1)identify the specific combination of epigenetic parameters involved in transmission of HFD/-Ex-induced epimutations from sperm to the ensuing fetus, 2) reveal the extent to, and mechanisms by, which resulting epimutations in the F1 fetus are propagated to developing somatic and germ cell lineages and on into the immature and adult offspring, 3) determine the extent of intercellular homo- versus hetero-geneity of HFD/-Ex-induced epimutations in spermatogenic cells of F0 sires and in relevant germ and somatic cell types in their F1 offspring, 4) discern the mechanisms by which inherited epimutations contribute to dysregulated gene expression in tissues relevant to aberrant phenotypes in the offspring, 5)elucidate dysregulated pathways responsible for defective or disease states among offspring of HFD/-Ex males, and 6)determine the extent to which the incidence of all of these deleterious effects can be reduced by transition of HFD/-Ex males to a normal (healthy) diet + exercise (ND/+Ex).
