C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line. C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

In the male mouse germline, PIWI-interacting RNAs (piRNAs) bound to the PIWI protein MIWI2 guide the DNA methylation of young active transposable elements (TEs) through SPOCD1. We identified loss-of-function variants in the human SPOCD1 gene that cause male infertility and defective TE silencing. One of the SPOCD1 pathogenic alleles encodes a truncated protein that lacks the conserved carboxy-terminus. We discovered that this deleted region interacts with C19ORF84. In mouse foetal germ cells, C19ORF84 is a nuclear protein that is required for the association of SPOCD1 with DNMT3L, an essential component of the de novo methylation machinery. In summary, we found a conserved role for SPOCD1 in safeguarding the continuity of the human germline and discovered C19ORF84, an uncharacterised protein essential for orchestrating piRNA-directed DNA methylation. Overall design: Examination of piRNA expression profiles in control (C19orf84+/-) and C19orf84-/- foetal testes as well as RNA expression profiles in wild-type and C19orf84-/- P20 testis.