Mechanisms of Genomic Imprinting

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Imprinted genes exhibit somatic parental specific monoallelic expression. The epigenetic determinants of imprinted gene expression are not fully understood and cannot be solely explained based on CpG methylation-it is not known what mechanism initiates DNA methylation at the imprinting control regions. Chromatin differences at imprinted genes, such as allele-specific \n vivo protein factor binding and/or histone covalent modifications are associated with-and constitute a layer of-cell memory for a number of imprinted genes in somatic cells, but no in vivo evidence exists of such differences or their role at the imprinting control regions in male or female germ-cells. These differences may exist before gonad-specific DNA methylation, and may, therefore, be required for imprint establishment. Such preexisting "primary chromatin differences" in chromatin composition can only be revealed by the analysis of germ cells at the window of time when methylation imprints are attained. Our studies will test the hypothesis, that "primary chromatin differences" between male and female germ cells exist and may be required for DNA methylation imprint establishment at the imprinting control regions. We will analyze the chromatin structure of the H19/lgf2 imprinting control region in normal and mutant somatic cells and also during male and female germ cell development in order to reveal the "primary chromatin difference(s) and confirm the role of these "primary chromatin differences" in imprint establishment. These studies are related to human health in that genomic imprinting underlies a number of human diseases, such as Beckwith-Wiedemann syndrome and Wilm's tumor. Definition of genomic imprinting at a fundamental level should shed further light on the genetic and epigenetic basis of human diseases associated with imprinting failure.