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Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation

Abstract

Canalization, also known as developmental robustness, describes an organism's ability to produce the same phenotype despite genotypic variations and environmental influences1,2. In Drosophila, Hsp90, the trithorax-group proteins and transposon silencing have been previously implicated in canalization3,4. Despite this, the molecular mechanism underlying canalization remains elusive. Here using a Drosophila eye-outgrowth assay sensitized by the dominant Krirregular facets-1(KrIf-1) allele3, we show that the Piwi-interacting RNA (piRNA) pathway, but not the short interfering RNA or micro RNA pathway, is involved in canalization. Furthermore, we isolated a protein complex composed of Hsp90, Piwi and Hop, the Hsp70/Hsp90 organizing protein homolog, and we demonstrated the function of this complex in canalization. Our data indicate that Hsp90 and Hop regulate the piRNA pathway through Piwi to mediate canalization. Moreover, they point to epigenetic silencing of the expression of existing genetic variants and the suppression of transposon-induced new genetic variation as two major mechanisms underlying piRNA pathway-mediated canalization.

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Figure 1: Maternal Piwi is an enhancer of ectopic outgrowth phenotype.
Figure 2: Biochemical isolation of Hop as an interactor of Piwi.
Figure 3: Hop is a maternal enhancer of the eye outgrowth phenotype.
Figure 4: Germline transmission of Piwi- and Hop-induced mutations.
Figure 5: Hsp90-dependent phosphorylation of Piwi.
Figure 6: A schematic illustration for the role of the Hsp90-Hop-Piwi complex in canalization.

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References

  1. Waddington, C.H. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).

    Article  Google Scholar 

  2. Waddington, C.H. Canalization of development and genetic assimilation of acquired characters. Nature 183, 1654–1655 (1959).

    Article  CAS  Google Scholar 

  3. Sollars, V. et al. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat. Genet. 33, 70–74 (2003).

    Article  CAS  Google Scholar 

  4. Specchia, V. et al. Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463, 662–665 (2010).

    Article  CAS  Google Scholar 

  5. Rutherford, S.L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).

    Article  CAS  Google Scholar 

  6. Queitsch, C., Sangster, T.A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002).

    Article  CAS  Google Scholar 

  7. Sangster, T.A., Lindquist, S. & Queitsch, C. Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. Bioessays 26, 348–362 (2004).

    Article  CAS  Google Scholar 

  8. Ruden, D.M., Garfinkel, M.D., Sollars, V.E. & Lu, X. Waddington's widget: Hsp90 and the inheritance of acquired characters. Semin. Cell Dev. Biol. 14, 301–310 (2003).

    Article  CAS  Google Scholar 

  9. Pal-Bhadra, M., Bhadra, U. & Birchler, J.A. RNAi related mechanisms affect both transcriptional and posttranscriptional transgene silencing in Drosophila. Mol. Cell 9, 315–327 (2002).

    Article  CAS  Google Scholar 

  10. Pal-Bhadra, M. et al. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303, 669–672 (2004).

    Article  CAS  Google Scholar 

  11. Grimaud, C. et al. RNAi components are required for nuclear clustering of Polycomb group response elements. Cell 124, 957–971 (2006).

    Article  CAS  Google Scholar 

  12. Brower-Toland, B. et al. Drosophila PIWI associates with chromatin and interacts directly with HP1a. Genes Dev. 21, 2300–2311 (2007).

    Article  CAS  Google Scholar 

  13. Yin, H. & Lin, H. An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster. Nature 450, 304–308 (2007).

    Article  CAS  Google Scholar 

  14. Brennecke, J. et al. An epigenetic role for maternally inherited piRNAs in transposon silencing. Science 322, 1387–1392 (2008).

    Article  CAS  Google Scholar 

  15. Carrera, P. et al. A modifier screen in the eye reveals control genes for Kruppel activity in the Drosophila embryo. Proc. Natl. Acad. Sci. USA 95, 10779–10784 (1998).

    Article  CAS  Google Scholar 

  16. Rutherford, S.L. & Henikoff, S. Quantitative epigenetics. Nat. Genet. 33, 6–8 (2003).

    Article  CAS  Google Scholar 

  17. Bergman, A. & Siegal, M.L. Evolutionary capacitance as a general feature of complex gene networks. Nature 424, 549–552 (2003).

    Article  CAS  Google Scholar 

  18. Cox, D.N., Chao, A. & Lin, H. piwi encodes a nucleoplasmic factor whose activity modulates the number and division rate of germline stem cells. Development 127, 503–514 (2000).

    CAS  PubMed  Google Scholar 

  19. Carrigan, P.E., Riggs, D.L., Chinkers, M. & Smith, D.F. Functional comparison of human and Drosophila Hop reveals novel role in steroid receptor maturation. J. Biol. Chem. 280, 8906–8911 (2005).

    Article  CAS  Google Scholar 

  20. Blatch, G.L. & Lassle, M. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21, 932–939 (1999).

    Article  CAS  Google Scholar 

  21. Pratt, W.B. & Toft, D.O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).

    CAS  Google Scholar 

  22. Odunuga, O.O., Longshaw, V.M. & Blatch, G.L. Hop: more than an Hsp70/Hsp90 adaptor protein. Bioessays 26, 1058–1068 (2004).

    Article  CAS  Google Scholar 

  23. Mittelman, D., Sykoudis, K., Hersh, M., Lin, Y. & Wilson, J.H. Hsp90 modulates CAG repeat instability in human cells. Cell Stress Chaperones 15, 753–759 (2010).

    Article  CAS  Google Scholar 

  24. Camphausen, K. & Tofilon, P.J. Inhibition of Hsp90: a multitarget approach to radiosensitization. Clin. Cancer Res. 13, 4326–4330 (2007).

    Article  CAS  Google Scholar 

  25. Dote, H., Burgan, W.E., Camphausen, K. & Tofilon, P.J. Inhibition of hsp90 compromises the DNA damage response to radiation. Cancer Res. 66, 9211–9220 (2006).

    Article  CAS  Google Scholar 

  26. Noguchi, M. et al. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Biochem. Biophys. Res. Commun. 351, 658–663 (2006).

    Article  CAS  Google Scholar 

  27. Kalmykova, A.I., Klenov, M.S. & Gvozdev, V.A. Argonaute protein PIWI controls mobilization of retrotransposons in the Drosophila male germline. Nucleic Acids Res. 33, 2052–2059 (2005).

    Article  CAS  Google Scholar 

  28. Hermisson, J. & Wagner, G.P. The population genetic theory of hidden variation and genetic robustness. Genetics 168, 2271–2284 (2004).

    Article  Google Scholar 

  29. Lin, H. piRNAs in the germ line. Science 316, 397 (2007).

    Article  CAS  Google Scholar 

  30. Lin, H. & Yin, H. A novel epigenetic mechanism in Drosophila somatic cells mediated by Piwi and piRNAs. Cold Spring Harb. Symp. Quant. Biol. 73, 273–281 (2008).

    Article  CAS  Google Scholar 

  31. Cox, D.N. et al. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 12, 3715–3727 (1998).

    Article  CAS  Google Scholar 

  32. Lee, Y.S. et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117, 69–81 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Siomi Lab for Piwi, Aub, and Ago 3 antibodies; R. Carthew and Y. Sik-Lee for FRT-dcr-1/2 flies and M. Chinkers for the Hop antibody. We would also like to thank L. Liu and V. Shteyn for technical assistance; A. Szakmary for Piwi position effect variegation (PEV) assay (Supplementary Fig. 3b), the Lin lab members for their valuable comments and A. Horwich for stimulating discussion. This work is supported by the US National Institutes of Health Grant R01HD33760, the G. Harold and Leila Mathers Foundation and the Connecticut Stem Cell Research Fund (06SCD01, 06SCE01 and 08SCD-Yale-004) to H.L.

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V.K.G. and H.L. designed the project and wrote the paper. H.Y. made the initial observation that piwi mutations affect canalization. M.M.W. showed that Hop mutations enhance eye outgrowth phenotype. J.W. performed two-dimensional gel electrophoresis and X.A.H. assisted with column chromatography.

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Correspondence to Haifan Lin.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4 and Supplementary Table 1 (PDF 7205 kb)

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Gangaraju, V., Yin, H., Weiner, M. et al. Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation. Nat Genet 43, 153–158 (2011). https://doi.org/10.1038/ng.743

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