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Author Notes:

René F. Ketting, r.ketting@imb-mainz.de

J.S. and R.F.K. conceived the study and designed experiments. J.S. executed experiments and performed data analysis. S.D. and F.B. performed MS analysis. A.M.d.J.D. and A.S. performed smRNA-seq analysis. M.B. and V.O performed the CLEM experiments. A.W.B. performed PEI-1/2 studies in cell culture. D.H.N. and C.M.P. provided unpublished strains. E.J.G., S.P. and S.W.L. shared unpublished data on MO counts. R.F.K. supervised the project. J.S. and R.F.K. wrote the manuscript with input from all authors.

We thank the members of the Ketting laboratory for helpful discussions. We are grateful to Helge Grosshans for critical reading of the manuscript. A special thanks to Miroslav Dörr and Svenja Hellmann for excellent technical support. Clara Werner and Annabelle Dold of the IMB Genomics Core Facility are thanked for small RNA library preparation. We thank the IMB Media Laboratory, Microscopy, Proteomic and Genomic Core Facilities for consumables, equipment and experimental support. Simone Köhler and Martin Schorb are thanked for their help in CLEM sample preparation and visualization. Some strains were provided by the Caenorhabditis Genetics Center (CGC), funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We acknowledge the GenEvo RTG funded by the Deutsche Forschungsgemeinschaft (DFG) – 407023052/GRK2526/1 enabling the conception of this project. This work was supported by grants of the DFG KE 1888/1-1, KE1888/1-2 and KE 1888/6-1 (R.F.K.) and the National Institute of Health R35 GM119656 (C.M.P.), and T32 GM118289 (D.H.N.).

The authors declare no financial and non-financial competing interests.



  • Animals
  • Animals, Genetically Modified
  • Argonaute Proteins
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cytoplasmic Granules
  • Epigenesis, Genetic
  • Humans
  • Lipoylation
  • Male
  • Paternal Inheritance
  • Protein Processing, Post-Translational
  • Spermatozoa

Membrane-associated cytoplasmic granules carrying the Argonaute protein WAGO-3 enable paternal epigenetic inheritance in Caenorhabditis elegans

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Journal Title:

Nature Cell Biology


Volume 24, Number 2


, Pages 217-229

Type of Work:

Article | Post-print: After Peer Review


Epigenetic inheritance describes the transmission of gene regulatory information across generations without altering DNA sequences, enabling offspring to adapt to environmental conditions. Small RNAs have been implicated in this, through both the oocyte and the sperm. However, as much of the cellular content is extruded during spermatogenesis, it is unclear whether cytoplasmic small RNAs can contribute to epigenetic inheritance through sperm. Here we identify a sperm-specific germ granule, termed the paternal epigenetic inheritance (PEI) granule, that mediates paternal epigenetic inheritance by retaining the cytoplasmic Argonaute protein WAGO-3 during spermatogenesis in Caenorhabditis elegans. We identify the PEI granule proteins PEI-1 and PEI-2, which have distinct functions in this process: granule formation, Argonaute selectivity and subcellular localization. We show that PEI granule segregation is coupled to the transport of sperm-specific secretory vesicles through PEI-2 in an S-palmitoylation-dependent manner. PEI-like proteins are found in humans, suggesting that the identified mechanism may be conserved.
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