Journal article
C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line
A Zoch, G Konieczny, T Auchynnikava, B Stallmeyer, N Rotte, M Heep, RV Berrens, M Schito, Y Kabayama, T Schöpp, S Kliesch, B Houston, L Nagirnaja, MK O'Bryan, KI Aston, DF Conrad, J Rappsilber, RC Allshire, AG Cook, F Tüttelmann Show all
Molecular Cell | Published : 2024
Abstract
In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF8..
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Grants
Awarded by European Molecular Biology Laboratory
Funding Acknowledgements
We acknowledge the EMBL GeneCore facility in Heidelberg, Germany, for pre-paring the EM-seq dataset of P14 spermatogonia and sequencing all next-generation sequencing libraries. The authors thank David Kelly at the Well come Centre for Cell Biology Centre for Optical Instrumentation Laboratory(COIL) and Matthieu Vermeren at the Centre for Regenerative Medicine Imaging Core Facility for microscopy and instrumentation support; Christos Spanos at the Wellcome Centre for Cell Biology Proteomics Facility for support with mass spectrometry analysis; the Shared University Research Facilities(SURF) histology and histological imaging facility for support with histology of mouse samples; Fiona Rossi at the Centre for Regenerative Medicine Flow Cytometry Facility for handling cell sorting of spermatogonia; and Theresa O'Connor at the Centre for Regenerative Medicine Tissue Culture Facility for providing cell culture facilities. This project was funded by Wellcome Trust grant 106144 and 225237 (D.O'C.), Wellcome Trust grant 213612(R.V.B.), Wellcome Trust grant 200898 (A.G.C.), Wellcome Trust grant 103139 (J.R.), Wellcome Trust grant 095021 (R.C.A.), Wellcome Trust grant 200885 (R.C.A.), Wellcome Trust Core grant 203149 (Wellcome Centre for Cell Biology), Wellcome Trust multi-user equipment grant 108504 (Wellcome Centre for Cell Biology), German Research Foundation fellowship DFG ZO376/1-1 (A.Z.), German Research Foundation Clinical Research Unit ''MaleGerm Cells'' DFG CRU326, National Institutes of Health R01HD07864(D.F.C. and K.I.A.), and National Health and Medical Research Project grant APP1120356 (M.K.O'B., D.F.C., and K.I.A.).