Role of TEX15 in piRNA-directed de novo DNA methylation in the developing male germline

Abstract

The PIWI-interacting RNA (piRNA) pathway instructs DNA methylation of young active transposable elements (TEs) in the male germline via the PIWI protein MIWI2. In the proposed model MIWI2 is recruited to transcriptionally active TE loci via base pairing between a piRNA and nascent transcript, however the downstream mechanism as well as effector proteins required by MIWI2 in directing de novo methylation of TEs, have yet to be fully elucidated. Recent advances in the investigation of the MIWI2 interactome have uncovered several candidates to be involved in this process, one of which is TEX15. This study shows that MIWI2 associates with TEX15 in foetal gonocytes, that it is a predominantly nuclear protein not required for piRNA biogenesis, but essential for piRNA-directed TE de novo methylation and silencing. Furthermore, its N-terminal domain of unknown function (DUF3715) is found yet in another protein involved in TE silencing. Here I show that not only sequence but the function of this domain is highly conserved between TEX15 and TASOR and that this conservation reaches back in evolution as far as zebrafish. In summary, TEX15 is an essential executor of mammalian piRNA-directed de novo DNA methylation and its N-terminal domain is specialized for TE silencing.