Epitranscriptomic regulation and genome stability in meiosis and the preimplantation embryo

One of the most profound changes in the life of an organism is the remarkable reprogramming of mRNA transcripts in the early preimplantation embryo. mRNA is a messenger molecule between the gene located on the DNA molecule (chromosome) and the protein to be synthesized. The reliance on presynthesized mRNAs is a unique feature of meiosis and shortly after fertilization, embryos cross a stage during which developmental control is handed from maternally supplied mRNAs from the mature oocyte to zygotic transcribed mRNAs. Studies in model organisms assign unique roles for dynamic mRNA modifications in meiosis and for the precise configuration of the early embryo. We here propose to study in detail the temporal and spatial role of dynamic and reversible methylations in mRNA in meiosis and in the preimplantation embryo. We will combine recent achievement in epigenetic single-cell analysis and focus on single-cell and single embryo analysis to gain detailed information regarding the methylation and demethylation of individual mRNAs, and the destiny of these mRNAs when bound to reader proteins. The most recent discovery of epitranscriptomic regulation of R-loop (three-stranded RNA/DNA hybrid structures) will be pursued to elucidate its role in genome (in)stability and the potential regulation of the mutational load of meiotic cells.

One of the most profound changes in the life of an organism is the remarkable reprogramming of mRNA transcripts in the early preimplantation embryo. The reliance on presynthesized mRNAs is a unique feature of meiosis and shortly after fertilization, embryos cross a stage during which developmental control is handed from maternally supplied mRNAs from the mature oocyte to zygotic transcribed mRNAs; the maternal-to-zygotic transition (MZT). Studies in model organisms assign unique roles for dynamic mRNA modifications in meiosis and for the precise configuration of the early embryo. We here propose to study in detail the temporal and spatial role of dynamic and reversible methylations in mRNA in meiosis and through the MZT in the preimplantation embryo. We will combine recent achievement in epigenetic single-cell analysis and focus on single-cell and single embryo analysis to gain detailed information regarding the methylation and demethylation of individual mRNAs, and the destiny of these mRNAs when bound to reader proteins. The most recent discovery of epitranscriptomic regulation of R-loop (three-stranded RND/DNA hybrid structures) will be pursued to elucidate its role in genome (in)stability and the potential regulation of the mutational load of meiotic cells. Methylation of DNA and histone residues regulates transcription and the discoveries of demethylases that remove these marks have led to a tremendous progress in our understanding of dynamic methylation in gene regulation. Post-transcriptional RNA modifications were identified several decades ago, but the reversible nature of RNA modifications has only recently been discovered. Our studies will focus on the role of readers and erasers of these dynamic methyl marks. The project will combine our recent studies on the epigenetic regulation at the MZT, our contribution to the discovery of novel epitranscriptomic marks and our early studies on genome stability and DNA repair.