Grant: Operating Grant

The progenitors of the sperm and egg, known as primordial germ cells (PGCs), first appear during early embryonic development. These cells can be recognized and isolated based on the presence of a unique set of proteins within or on the cell surface. Early in embryonic developmental, these cells undergo dramatic changes in the nucleus, coincident with the induction of a set of genes that are required for further differentiation into mature egg or sperm and the silencing of specific genes that are not necessary or may hinder this process. Methylation of DNA plays an important role in gene regulation and defects in DNA methylation can disrupt this regulatory cascade, leading to cancer, infertility and developmental diseases, such as Beckwith-Wiedemann and Prader-Willi syndromes. However, due to the relatively small number of PGCs present in the early embryo, studying the process of gene regulation at this developmental stage has proven very difficult. Using the mouse as a model for human development, we will employ new genomic tools optimized for use on small numbers of cells, including genome-wide sequencing to simultaneously study the changes in expression of many genes and parasitic elements (so called junk DNA) in the genome at this critical developmental stage. Using engineered mice that are deficient in specific proteins shown previously to play a role in turning off other genes in adult tissues and to cause infertility and other developmental defects, we will study the role of these proteins in regulating DNA methylation in PGCs and identify those genes that are specifically aberrantly expressed in PGCs deficient in these proteins. These experiments may yield novel drug targets for developmental disorders as well as specific cancers in which perturbing or promoting DNA methylation is of therapeutic value.