Paramutation in Drosophila linked to emergence of a piRNA-producing locus

Abstract

A paramutation is an epigenetic interaction between two alleles of a locus, through which one allele induces a heritable modification in the other allele without modifying the DNA sequence1,2. The paramutated allele itself becomes paramutagenic, that is, capable of epigenetically converting a new paramutable allele. Here we describe a case of paramutation in animals showing long-term transmission over generations. We previously characterized a homology-dependent silencing mechanism referred to as the trans-silencing effect (TSE), involved in P-transposable-element repression in the germ line3,4,5. We now show that clusters of P-element-derived transgenes that induce strong TSE6,7 can convert other homologous transgene clusters incapable of TSE into strong silencers, which transmit the acquired silencing capacity through 50 generations. The paramutation occurs without any need for chromosome pairing between the paramutagenic and the paramutated loci, and is mediated by maternal inheritance of cytoplasm carrying Piwi-interacting RNAs (piRNAs) homologous to the transgenes. The repression capacity of the paramutated locus is abolished by a loss-of-function mutation of the aubergine gene involved in piRNA biogenesis, but not by a loss-of-function mutation of the Dicer-2 gene involved in siRNA production. The paramutated cluster, previously producing barely detectable levels of piRNAs, is converted into a stable, strong piRNA-producing locus by the paramutation and becomes fully paramutagenic itself. Our work provides a genetic model for the emergence of piRNA loci, as well as for RNA-mediated trans-generational repression of transposable elements.

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Figure 1: Maternal inheritance of P-1152 and T-1 repression capacities correlates with the presence of T-1 - or P-1152 -derived piRNAs in ovaries of female progeny.
Figure 2: Epigenetic induction of BX2 by T-1.
Figure 3: BX2* paramutation occurs and is associated to the production of small RNAs by the BX2 cluster.
Figure 4: Paramutated BX2* is paramutagenic.

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Primary accessions

Sequence Read Archive

Data deposits

SmallRNA sequences have been deposited at the National Center for Biotechnology Information under accession SRP012172.

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Acknowledgements

We thank O. Sismeiro, J.-Y. Copée, E. Mouchel-Vielh, V. Ribeiro, C. Pappatico and P. Graça for technical assistance, D. Dorer, S. Henikoff and the Bloomington Stock Center for providing stocks, and flybase.org for providing databases. We thank T. Josse for preliminary experiments. We thank J.-R. Huynh, V. Colot, N. Randsholt, A.-M. Pret, C. Carré and F. Peronnet for critical reading of the manuscript. S.R. thanks D. Anxolabéhère and M. Lehmann for previous help. This work was supported by fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche to A.d.V. and C.H., from the Fondation pour la Recherche Médicale to A.d.V., from the Association Nationale de la Recherche (ANR) to A.-L.B., and by grants from the Association pour la Recherche contre le Cancer to S.R. and from the ANR (project “Nuclear endosiRNAs”) to C.A.

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Genetic experiments were conceived by A.d.V., A.B. and S.R., and performed by A.d.V., A.B., C.H., V.D., L.T. and S.R. L.T. conceived and performed molecular mapping of the clusters and Southern blot analysis. Deep-sequencing analysis was conceived by A.d.V., A.-L.B., S.R. and C.A., and performed by A.d.V. and A.-L.B. Bioinformatic analysis was conceived and performed by C.A. RT–qPCR was conceived and performed by A.B. S.R., A.d.V., A.B. and C.A. wrote the paper and all authors discussed the results.

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Correspondence to Christophe Antoniewski or Stéphane Ronsseray.

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de Vanssay, A., Bougé, A., Boivin, A. et al. Paramutation in Drosophila linked to emergence of a piRNA-producing locus. Nature 490, 112–115 (2012). https://doi.org/10.1038/nature11416

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