Unveiling of SPOCD1: an essential executor of piRNA directed De Novo DNA methylation in Mammals

SPOCD1 is a key executor for piRNA-directed DNA methylation
The acquisition of the mammalian germline by the soma presents the germline with a challenge: the need to reset and erase genomic methylation1. In the male germline RNA-directed DNA methylation is responsible for silencing young transposable elements. The PIWI proteins MIWI2 (PIWIL4), and their associated PIWI-interacting RNAs(piRNAs), instruct TE DNA methylation3,5. The piRNAs have been proposed to bind MIWI2 with nascent TE transcriptions. However, the mechanism through which MIWI2 directs the de novo TE methylation remains poorly understood. We define the MIWI2 interactome in foetal gonocytes undergoing de-novo genome methylation. SPOCD1, a novel MIWI2-associated protein, is also identified as essential for young TE methylation. Spocd1 loss in mice leads to male-specific infertility, but does not affect piRNA biogenesis or localization of MIWI2 in the nucleus. SPOCD1 has a nuclear location and is expressed only during the de novo methylation of genomes. SPOCD1 was purified in vivo together with DNMT3L, DNMT3A and NURD/BAF chromatin remodeling complexes. We propose a mechanism whereby the tethering MIWI2 to an nascent transcript recruits de novo methylation and repressive chromatin remodeling activities through SPOCD1. We have, in summary, identified a novel and crucial executor for mammalian DNA methylation directed by piRNA.


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