Epigenetics is the study of reveresible heritable changes in gene function that occur without a change in the sequence of nuclear DNA. It is also the study of the processes involved in the unfolding development of an organism. In both cases, the object of study includes how gene regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next - that is (from the Greek prefix), 'in addition to' the genetic information encoded in the DNA.
Why this Project:
Radiation-induced bystander effect is a phenomenon where cells not directly exposed to ionizing radiation still display an increase in chromosomal and genomic instability. Such changes can lead to either cell death or increased susceptibility to chronic adult diseases such as cancer. DNA hypomethylation and chromatin deacetylation are reversible inheritable changes in gene function that result in genomic instability, and are the earliest detectable events in carcinogenesis. Nevertheless, the role of this genetic deregulationin the etiology of low dose radiation-induced cellular damage is presently unclear. The epigenome is particularly vulnerable to changes by environmental factors during the formation of the embryobecause the DNA synthetic rate is high, and the elaborate DNA methylation patterning required for normal organ development is established early in gestation.
Project Goals:
Specifically, we will determine if maternal exposure to a chronic low dose of ionizing radiation during pregnancy
- alters coat color and the incidence of obesity and cancer in Avy offspring by changing DNA methylation;
- alters the extent of a tail kink in AxinFu offspring by changing DNA methylation;
- results in biallelic expression of the imprinted Igf2 gene by causing loss of imprinting; and
- deregulates the expression of other imprinted genes by causing genome-wide epigenetic dysregulation.
Experimental Approach :
The overall hypothesis is that exposure to chronic low doses of ionizing radiation during gestation can affect the adult phenotype by altering DNA methylation and gene expression patterns. We will use viable yellow Agouti (Avy) and Axin fused (AxinFu) mice to test this novel postulate because they are exquisitely sensitive "epigenetic biosensors" for environmental agents that alter adult phenotypes through modification of the epigenome.
Expected Outcomes:
The studies proposed in this application are of critical importance because they will determine, for the first time, if exposure to low doses and low dose rates of ionizing radiation during gestation can alter the adult phenotype via epimutations, changes in DNA methylation that could potentially be inhibited by maternal dietary methyl donor supplementation.
