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

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Authors

Zoch, A., Konieczny, G., Auchynnikava, T., Stallmeyer, B., Rotte, N., Heep, M., Berrens, R.V., Schito, M., Kabayama, Y.,  Schöpp, T., Kliesch, S., Houston, B., Nagirnaja, L., O’Bryan, M.K., Aston, K.I., Conrad, D.F., Rappsilber, J., Allshire, R.C., Cook, A.G., Tüttelmann, F., and O’Carroll, D.

Summary of Paper by Melanie Lim,  Marston Lab

Transposons are genetic elements with “wings”, moving throughout the genome at the expense of protein-coding genes and regulatory elements. Addition of methyl groups to DNA limits transposon movement, yet during germ cell development methylation marks are erased genome-wide. The threat from expressed transposons is overcome by an RNA-based (piRNA) pathway – piRNAs guide PIWI proteins and a DNA methyltransferase to mediate transposon methylation.

Prior work identified SPOCD1 protein as an intermediary linking piRNA and DNA methylation pathways, although mechanistic details were lacking. Additionally, while mutations in the human piRNA pathway were associated with male infertility, it was unclear if these mutations also affected transposon silencing. Donal O’Carroll led a team of researchers to address both questions.

In collaborative effort, three infertile men with distinct SPOCD1 mutations were identified. One SPOCD1 allele was predicted to truncate the SPOCD1 C-terminus, with the missing part predicted to bind other proteins. A SPOCD1-interactor and previously uncharacterised protein C19ORF84 piqued the researchers’ interest – it is expressed exclusively during de novo methylation in mice testes. A series of imaging and biochemical experiments confirmed SPOCD1, C19ORF84 and DNMT3C (de novo DNA methyltransferase) associate. This is the first in vivo evidence linking the piRNA pathway and DNA methylation machinery.

Following on from this, the authors found that C19ORF84 absence caused the mis-expression of transposons, normally repressed in mice testicular tissue. This correlated with the lack of methylation at transposon promoters. Finally, it was shown in vivo that C19ORF84 was necessary for SPOCD1 and DNMT3L recruitment within mouse testes. Overall, this work defines C19ORF84 as an adaptor, guiding piRNA-directed DNA methyltransferases to drive transposon methylation and maintain germ line genome integrity.

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