Histone Demethylase Control of Post Implantation Development

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ABSTRACT Functional specialization in a multicellular organism arises when cell fate is established by a specific gene expression pattern. Epigenetic modifications working with transcription factors enable cell identity. During early development a few cells migrate at the epiblast stage to the gonad to become Primordial germ cells (PGCs), which are the precursors of gametes. PGCs undergo an ordered series of global epigenetic changes that decimates the repressive modifications: H3 lysine 9 methylation (H3K9me2) and DNA methylation, which suppress expression of repetitive elements to maintain genomic integrity, and is replaced by other marks such as H2A/H4 arginine methylation (H2A/H4R3me2). How the precise temporal regulation of these epigenetic events is coordinated and their interdependence remains poorly understood. Incorrect or partial erasure at specific locations could lead to imprinting defects as well as inadvertent transgenerational inheritance. We have discovered that the H3K9me2 demethylase, KDM3B, controls DNA demethylation by the Tet enzymes and interacts with PRMT5, a H2A/H4R3 methyltransferase. Despite H3K9me2 being a repressive histone modification, we have found that KDM3B and KDM3A interact with mRNA processing machinery. Taken together we hypothesize that proteins of the KDM3 family orchestrate post-implantation development to PGCs by epigenetic and post-transcriptional mechanisms, which will be investigated in this proposal.