Germ Granules Govern Small RNA Inheritance
Authors: Uri Seroussi
Itay Ben Shushan
Hila Gingold
Olga Antonova
Ronen Zaidel-Bar
Guy Weintraub
Yael Mor
Anat Nitzan
Itamar Lev
Oded Rechavi
Ornit Bhonkar
Itai Antoine Toker
Julie M Claycomb
Sarit Anava
Journal: Current Biology (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: P granules; RNAi; endogenous siRNAs; germ granules; hrde-1
Affiliations: Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ., Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel., Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel., Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.

Abstract:  In C. elegans nematodes, components of liquid-like germ granules were shown to be required for transgenerational small RNA inheritance. Surprisingly, we show here that mutants with defective germ granules can nevertheless inherit potent small RNA-based silencing responses, but some of the mutants lose this ability after many generations of homozygosity. Animals mutated in pptr-1, which is required for stabilization of P granules in the early embryo, display extraordinarily strong heritable RNAi responses, lasting for tens of generations. Intriguingly, the RNAi capacity of descendants derived from mutants defective in the core germ granule proteins MEG-3 and MEG-4 is determined by the genotype of the ancestors and changes transgenerationally. Further, whether the meg-3/4 mutant alleles were present in the paternal or maternal lineages leads to different transgenerational consequences. Small RNA inheritance, rather than maternal contribution of the germ granules themselves, mediates the transgenerational defects in RNAi of meg-3/4 mutants and their progeny. Accordingly, germ granule defects lead to heritable genome-wide mis-expression of endogenous small RNAs. Upon disruption of germ granules, hrde-1 mutants can inherit RNAi, although HRDE-1 was previously thought to be absolutely required for RNAi inheritance. We propose that germ granules sort and shape the RNA pool, and that small RNA inheritance maintains this activity for multiple generations. 

Retracted: No

PubPeer comments:
 Figure 4A: The image used to represent the progeny of crossed animals is the same as used on Figure 1D to represent the meg-3 4 mutant. Could authors please check if that was expected? ![file] , 
 After re-checking our files, we concluded that we inadvertently used the wrong image in Figure 1D. Both Figures 1D-right and 4B-C-red depict meg-3 4 mutants, meaning that the granule-related phenotype is undistinguishable and the file names were resembling, all contributing to our mistake during incorporation of the images while preparing Figure 1. We still have all the raw images of embryos used in the study, and will upload them to the online database appearing below within a few days, and even beforehand, we can send them to anyone who is interested (and are happy to discuss via email or phone any other questions). [https: figshare.com projects Germ_Granules_Govern_Small_RNA_Inheritance 113916. ](http: ) Additional notes: Specific labels and legend describing the images in Figure 1D are correct (i.e., the depicted embryos are meg-3 4 mutants). As mentioned in the original paper, the embryonic granule morphology phenotype of meg-3 4 mutants that we show in Figure 1D is a control and not a novel discovery. Similar images depicting it can be found in papers by other research groups published both before and after our article. For example Wang JT et al. eLife 2014 ; Wan G et al. Nature 2018 ; Dodson AE Kennedy S Dev Cell 2019 ; Ouyang JPT et al. Dev Cell 2019. The corresponding authors, Itamar Lev, Itai A. Toker, Yael Mor, Oded Rechavi. ,