Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila

Nature volume 426, pages 78–83 (2003)Cite this article

Abstract

Steroid hormones fulfil important functions in animal development. In Drosophila, ecdysone triggers moulting and metamorphosis through its effects on gene expression1. Ecdysone works by binding to a nuclear receptor, EcR, which heterodimerizes with the retinoid X receptor homologue Ultraspiracle2,3. Both partners are required for binding to ligand or DNA4,5,6. Like most DNA-binding transcription factors, nuclear receptors activate or repress gene expression by recruiting co-regulators, some of which function as chromatin-modifying complexes7,8. For example, p160 class coactivators associate with histone acetyltransferases and arginine histone methyltransferases9. The Trithorax-related gene of Drosophila encodes the SET domain protein TRR. Here we report that TRR is a histone methyltransferases capable of trimethylating lysine 4 of histone H3 (H3-K4). trr acts upstream of hedgehog (hh) in progression of the morphogenetic furrow, and is required for retinal differentiation. Mutations in trr interact in eye development with EcR, and EcR and TRR can be co-immunoprecipitated on ecdysone treatment. TRR, EcR and trimethylated H3-K4 are detected at the ecdysone-inducible promoters of hh and BR-C in cultured cells, and H3-K4 trimethylation at these promoters is decreased in embryos lacking a functional copy of trr. We propose that TRR functions as a coactivator of EcR by altering the chromatin structure at ecdysone-responsive promoters.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TRR is a nuclear protein that methylates H3-K4.
Figure 2: TRR interacts genetically and associates in vitro and in vivo with components of the ecdysone receptor complex.
Figure 3: The role of trr during eye development.
Figure 4: Molecular effects of ecdysone.

Similar content being viewed by others

References

  1. Riddiford, L. M. Hormone receptors and the regulation of insect metamorphosis. Receptor 3, 203–209 (1993)

    CAS  Google Scholar 

  2. Oro, A. E., McKeown, M. & Evans, R. M. Relationship between the product of the Drosophila ultraspiracle locus and the vertebrate retinoid X receptor. Nature 347, 298–301 (1990)

    Article  ADS  CAS  Google Scholar 

  3. Koelle, M. R. et al. The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily. Cell 67, 59–77 (1991)

    Article  CAS  Google Scholar 

  4. Thomas, H. E., Stunnenberg, H. G. & Stewart, A. F. Heterodimerization of the Drosophila ecdysone receptor with retinoid X receptor and ultraspiracle. Nature 362, 471–475 (1993)

    Article  ADS  CAS  Google Scholar 

  5. Yao, T. P., Segraves, W. A., Oro, A. E., McKeown, M. & Evans, R. M. Drosophila ultraspiracle modulates ecdysone receptor function via heterodimer formation. Cell 71, 63–72 (1992)

    Article  CAS  Google Scholar 

  6. Yao, T. P. et al. Functional ecdysone receptor is the product of EcR and Ultraspiracle genes. Nature 366, 476–479 (1993)

    Article  ADS  CAS  Google Scholar 

  7. Hermanson, O., Glass, C. K. & Rosenfeld, M. G. Nuclear receptor coregulators: multiple modes of modification. Trends Endocrinol. Metab. 13, 55–60 (2002)

    Article  CAS  Google Scholar 

  8. Stallcup, M. R. Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene 20, 3014–3020 (2001)

    Article  CAS  Google Scholar 

  9. Lee, Y. H., Koh, S. S., Zhang, X., Cheng, X. & Stallcup, M. R. Synergy among nuclear receptor coactivators: selective requirement for protein methyltransferase and acetyltransferase activities. Mol. Cell. Biol. 22, 3621–3632 (2002)

    Article  CAS  Google Scholar 

  10. Sedkov, Y. et al. Molecular genetic analysis of the Drosophila trithorax-related gene which encodes a novel SET domain protein. Mech. Dev. 82, 171–179 (1999)

    Article  CAS  Google Scholar 

  11. Katsani, K. R., Arredondo, J. J., Kal, A. J. & Verrijzer, C. P. A homeotic mutation in the trithorax SET domain impedes histone binding. Genes Dev. 15, 2197–2202 (2001)

    Article  CAS  Google Scholar 

  12. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000)

    Article  ADS  CAS  Google Scholar 

  13. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002)

    Article  ADS  CAS  Google Scholar 

  14. Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002)

    Article  ADS  CAS  Google Scholar 

  15. Beisel, C., Imhof, A., Greene, J., Kremmer, E. & Sauer, F. Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1. Nature 419, 857–862 (2002)

    Article  ADS  CAS  Google Scholar 

  16. Smith, S. T. et al. Modulation of heat shock gene expression by the TAC1 chromatin modifying complex. Nature Cell Biol (submitted)

  17. Heery, D. M., Kalkhoven, E., Hoare, S. & Parker, M. G. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997)

    Article  ADS  CAS  Google Scholar 

  18. Kuzin, B., Tillib, S., Sedkov, Y., Mizrokhi, L. & Mazo, A. The Drosophila trithorax gene encodes a chromosomal protein and directly regulates the region-specific homeotic gene fork head. Genes Dev. 8, 2478–2490 (1994)

    Article  CAS  Google Scholar 

  19. Zelhof, A. C., Ghbeish, N., Tsai, C., Evans, R. M. & McKeown, M. A role for ultraspiracle, the Drosophila RXR, in morphogenetic furrow movement and photoreceptor cluster formation. Development 124, 2499–2506 (1997)

    CAS  Google Scholar 

  20. Brennan, C. A., Ashburner, M. & Moses, K. Ecdysone pathway is required for furrow progression in the developing Drosophila eye. Development 125, 2653–2664 (1998)

    CAS  Google Scholar 

  21. Cherbas, L., Hu, X., Zhimulev, I., Belyaeva, E. & Cherbas, P. EcR isoforms in Drosophila: testing tissue-specific requirements by targeted blockade and rescue. Development 130, 271–284 (2003)

    Article  CAS  Google Scholar 

  22. Tsai, C. C., Kao, H. Y., Yao, T., McKeown, M. & Evans, R. M. SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development. Mol. Cell 4, 175–186 (1999)

    Article  CAS  Google Scholar 

  23. Hu, X., Cherbas, L. & Cherbas, P. Transcription activation by the ecdysone receptor: Identification of activation functions in EcR/USP. Mol. Endocrinol. 17, 716–731 (2003)

    Article  CAS  Google Scholar 

  24. Ghbeish, N. & McKeown, M. Analyzing the repressive function of ultraspiracle, the Drosophila RXR, in Drosophila eye development. Mech. Dev. 111, 89–98 (2002)

    Article  CAS  Google Scholar 

  25. Treisman, J. E. & Rubin, G. M. wingless inhibits morphogenetic furrow movement in the Drosophila eye disc. Development 121, 3519–3527 (1995)

    CAS  Google Scholar 

  26. Ma, C., Zhou, Y., Beachy, P. A. & Moses, K. The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell 75, 927–938 (1993)

    Article  CAS  Google Scholar 

  27. Heberlein, U., Wolff, T. & Rubin, G. M. The TGFβ homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina. Cell 75, 913–926 (1993)

    Article  CAS  Google Scholar 

  28. Treisman, J. E., Luk, A., Rubin, G. M. & Heberlein, U. eyelid antagonizes wingless signaling during Drosophila development and has homology to the Bright family of DNA-binding proteins. Genes Dev. 11, 1949–1962 (1997)

    Article  CAS  Google Scholar 

  29. Chanut, F., Luk, A. & Heberlein, U. A screen for dominant modifiers of roDom, a mutation that disrupts morphogenetic furrow progression in Drosophila, identifies groucho and hairless as regulators of atonal expression. Genetics 156, 1203–1217 (2000)

    CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Thummel, F. Kafatos, J. Treisman, M. Fujioka, T. Kornberg and Y. Zhang for antibodies, mutant stocks and mutant histones; and J. Kumar and F. R. Turner for the scanning electron microscopy images. This work was supported by a grant from the National Cancer Institute (to A.M.); an NIH award (to J.B.J.); a grant from the NSF (to P.C.); and an NIH training grant (to E.C.).

Author information

Author notes

  1. Yurii Sedkov and Elizabeth Cho: These authors contributed equally to this work

Authors and Affiliations

  1. Kimmel Cancer Center, Thomas Jefferson University, Pennsylvania, 19107, Philadelphia, USA

    Yurii Sedkov, Elizabeth Cho, Svetlana Petruk, Sheryl T. Smith, James B. Jaynes & Alexander Mazo

  2. Department of Biology, Indiana University, Indiana, 47405-3700, Bloomington, USA

    Lucy Cherbas & Peter Cherbas

  3. Department of Biological Sciences, Southern Methodist University, Texas, 75275-0376, Dallas, USA

    Richard S. Jones

  4. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Eli Canaani

Authors
  1. Yurii Sedkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Svetlana Petruk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucy Cherbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sheryl T. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard S. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Cherbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eli Canaani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James B. Jaynes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexander Mazo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Mazo.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sedkov, Y., Cho, E., Petruk, S. et al. Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila. Nature 426, 78–83 (2003). https://doi.org/10.1038/nature02080

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02080

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing