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SPOCD1 is an essential executor of piRNA-directed 1 de novo DNA methylation

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    Rights statement: This is the accepted version of the following article: Zoch, A., Auchynnikava, T., Berrens, R.V. et al. SPOCD1 is an essential executor of piRNA-directed de novo DNA methylation. Nature (2020). https://doi.org/10.1038/s41586-020-2557-5, which has been published in final form at https://www.nature.com/articles/s41586-020-2557-5.

    Accepted author manuscript, 11.1 MB, PDF document

Original languageEnglish
Pages (from-to)635-639
Number of pages5
JournalNature
Volume584
Issue number7822
Early online date16 Jul 2020
DOIs
Publication statusPublished - 27 Aug 2020

Abstract

In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge, the necessity to erase and reset genomic methylation. In the malegermline RNA-directed DNA methylation silences young active transposable elements(TEs)2-4. The PIWI protein MIWI2 (PIWIL4) and its associated PIWI-interacting RNAs(piRNAs) instruct TE DNA methylation. PiRNAs are proposed to tether MIWI2 tonascent TE transcripts, however the mechanism by which MIWI2 directs de novo TEmethylation is poorly understood but central to the immortality of the germline. Here, we define the interactome of MIWI2 in foetal gonocytes that are undergoing de novo genome methylation and identify a novel MIWI2-associated factor, SPOCD1, that is essential for young TE methylation and silencing. The loss of Spocd1 in mice results in male-specific infertility but impacts neither piRNA biogenesis nor localization of MIWI2 to the nucleus. SPOCD1 is a nuclear protein and its expression is restricted to the period of de novogenome methylation. We found SPOCD1 co-purified in vivo with DNMT3L and DNMT3A, components of the de novo methylation machinery as well as constituents of the NURD and BAF chromatin remodelling complexes. We propose a model where by tethering of MIWI2 to a nascent TE transcript recruits repressive chromatin remodelling activities and the de novo methylation apparatus through SPOCD1. In summary, we have identified a novel and essential executor of mammalian piRNA-directed DNA methylation.

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