**PLEASE NOTE – the deadline for requesting a funding pack from Darwin Trust has now passed and completed funding applications must be submitted to Darwin Trust by 19th January. We can still accept applications for this project from self-funding students.
In mammals, transposons are silenced throughout most of life by DNA methylation. The mammalian germline is derived from somatic cells early during development. To reset genomic DNA methylation patterns, genome demethylation and de novo methylation is required in germline cells as the embryo develops. In the male germline, the PIWI protein MIWI2, along with its associated small non-coding piRNAs, direct DNA methylation to silence young, active transposons (1). We have defined a high confidence MIWI2 interactome from gonocytes that are undergoing de novo DNA methylation. We identified two MIWI2-associated nuclear factors, TEX15 and SPOCD1, that are essential for piRNA-directed de novo TE methylation (2 and 3). The molecular function of TEX15 remains unknown but it likely acts upstream of SPOCD1 (2). SPOCD1 links MIWI2 to key components of the de novo methylation machinery as well as chromatin remodelling complexes (3). This discovery now permits the exploration of the molecular mechanisms and design principles underpinning piRNA-directed transposon methylation. In this project, we propose to define, through biochemical methods, what proteins directly interact with MIWI2 and the novel factors. We also propose to explore molecular and structural basis of key interactions. Finally, we aim to understand how these constituents of the complex contribute to function by employing mouse genetics to generate alleles that encode point mutations that uncouple the respective factors from their key interacting proteins. In summary, the goal of the proposed project is to define, mechanistically and at high resolution, this process that is essential for the immortality of the germline and the continuity of mammalian life.
https://www.wcb.ed.ac.uk/research/donal-ocarroll
https://www.ed.ac.uk/regenerative-medicine/research/donal-o-carroll
https://www.wcb.ed.ac.uk/research/cook
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