Histone demethylase control of primordial germ cell specification

Proposal Summary/Abstract During mouse embryonic development, approximately 40 cells in the post-implantation epiblast are designated as Primordial Germ Cells (PGCs) and destined to become sperm or egg. PGCs undergo global epigenetic remodeling, which is not seen in the surrounding somatic cells. The repressive histone modification H3K9me2 is depleted during PGC specification. In parallel, DNA is demethylated in two waves: a global erasure followed by a loci specific depletion. The only locations to escape this first wave of global erasure are a few germ cell specifying genes, imprinted loci, and transposable elements. How these loci are protected from the first phase of DNA demethylation is still unknown. Previous data from my thesis lab has shown that in somatic cell reprogramming to induced pluripotent stem cells, there is coordinated removal of the same repressive epigenetic marks of H3K9me2 and DNA methylation. I propose that H3K9me2 demethylases KDM3A and KDM3B have important roles in PGC development which I will investigate using an in vitro PGC-like cell differentiation model and Next-generation sequencing experiments. This research will elucidate the importance of removal of repressive modifications to prevent transgenerational epigenetic inheritance which could be disruptive to embryonic development, germ cell specification, and fertility.