@article{ef64ec62e0fd4979a68ff23dc457f730,
title = "P Granules Protect RNA Interference Genes from Silencing by piRNAs",
abstract = "P granules are perinuclear condensates in C. elegans germ cells proposed to serve as hubs for self/non-self RNA discrimination by Argonautes. We report that a mutant (meg-3 meg-4) that does not assemble P granules in primordial germ cells loses competence for RNA-interference over several generations and accumulates silencing small RNAs against hundreds of endogenous genes, including the RNA-interference genes rde-11 and sid-1. In wild type, rde-11 and sid-1 transcripts are heavily targeted by piRNAs and accumulate in P granules but maintain expression. In the primordial germ cells of meg-3 meg-4 mutants, rde-11 and sid-1 transcripts disperse in the cytoplasm with the small RNA biogenesis machinery, become hyper-targeted by secondary sRNAs, and are eventually silenced. Silencing requires the PIWI-class Argonaute PRG-1 and the nuclear Argonaute HRDE-1 that maintains trans-generational silencing of piRNA targets. These observations support a “safe harbor” model for P granules in protecting germline transcripts from piRNA-initiated silencing.",
keywords = "Argonautes, P granules, RNA-mediated interference, epigenetic silencing, piRNAs",
author = "Ouyang, {John Paul T.} and Andrew Folkmann and Lauren Bernard and Lee, {Chih Yung} and Uri Seroussi and Charlesworth, {Amanda G.} and Claycomb, {Julie M.} and Geraldine Seydoux",
note = "Funding Information: We thank the Johns Hopkins Neuroscience Research Multiphoton Imaging Core ( NS050274 ) and the Johns Hopkins Integrated Imaging Center ( S10OD023548 ) for excellent microscopy support. We thank the Phillips and Mello labs for strains; the Mello lab for help with analyzing CLASH data; the Miska lab for guidance with sRNA-seq; Anne Dodson and Scott Kennedy for sharing data before publication; and Charlotte Choi, Anne Dodson, Scott Kennedy, John Kim, Craig Mello, Eric Miska, the Baltimore Worm Club, and the Seydoux lab for many helpful discussions. J.P.T.O. thanks Taylor Swift for inspiration. J.P.T.O. was supported by the JHU SOM Biochemistry, Cellular, and Molecular Biology NIH training grant ( T32 GM007445 ). J.M.C., A.G.C., and U.S. were supported by funds from the Canadian Institutes of Health Research ( PJT156083 ). G.S. is an investigator of the Howard Hughes Institute. This work was also supported by the National Institutes of Health grant R37 HD037047 (to G.S.). Funding Information: We thank the Johns Hopkins Neuroscience Research Multiphoton Imaging Core (NS050274) and the Johns Hopkins Integrated Imaging Center (S10OD023548) for excellent microscopy support. We thank the Phillips and Mello labs for strains; the Mello lab for help with analyzing CLASH data; the Miska lab for guidance with sRNA-seq; Anne Dodson and Scott Kennedy for sharing data before publication; and Charlotte Choi, Anne Dodson, Scott Kennedy, John Kim, Craig Mello, Eric Miska, the Baltimore Worm Club, and the Seydoux lab for many helpful discussions. J.P.T.O. thanks Taylor Swift for inspiration. J.P.T.O. was supported by the JHU SOM Biochemistry, Cellular, and Molecular Biology NIH training grant (T32 GM007445). J.M.C. A.G.C. and U.S. were supported by funds from the Canadian Institutes of Health Research (PJT156083). G.S. is an investigator of the Howard Hughes Institute. This work was also supported by the National Institutes of Health grant R37 HD037047 (to G.S.). J.P.T.O. A.W.F. and L.B. conducted the experiments; J.P.T.O. A.W.F. L.B. C.Y.L. and G.S. analyzed the data; U.S. A.G.C. and J.M.C. constructed the GFP::CSR-1 and GFP::HRDE-1 strains; and J.P.T.O. and G.S. designed the experiments and wrote the paper. G.S. serves on the Scientific Advisory Board of Dewpoint Therapeutics, Inc. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = sep,
day = "23",
doi = "10.1016/j.devcel.2019.07.026",
language = "English (US)",
volume = "50",
pages = "716--728.e6",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",
}