Atrophin controls developmental signaling pathways via interactions with Trithorax-like

  1. Kelvin Yeung
  2. Ann Boija
  3. Edvin Karlsson
  4. Per-Henrik Holmqvist
  5. Yonit Tsatskis
  6. Ilaria Nisoli
  7. Damian B Yap
  8. Alireza Lorzadeh
  9. Michelle Moksa
  10. Martin Hirst
  11. Samuel Aparicio
  12. Manolis Fanto
  13. Per Stenberg
  14. Mattias Mannervik  Is a corresponding author
  15. Helen McNeill  Is a corresponding author
  1. University of Toronto, Canada
  2. Stockholm University, Sweden
  3. Umeå University, Sweden
  4. University College London, United Kingdom
  5. University of British Columbia, Canada
  6. King's College London, United Kingdom

Abstract

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atro's critical role in development and disease, relatively little is known about Atro's binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kelvin Yeung

    Department of Molecular Genetics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  2. Ann Boija

    Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  3. Edvin Karlsson

    Department of Molecular Biology, Umeå University, Umeå, Sweden
    Competing interests
    No competing interests declared.
  4. Per-Henrik Holmqvist

    Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  5. Yonit Tsatskis

    Department of Molecular Genetics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  6. Ilaria Nisoli

    Division of Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Damian B Yap

    Department of Molecular Oncology, University of British Columbia, Vancouver, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5370-4592
  8. Alireza Lorzadeh

    Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    No competing interests declared.
  9. Michelle Moksa

    Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    No competing interests declared.
  10. Martin Hirst

    Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    No competing interests declared.
  11. Samuel Aparicio

    Department of Molecular Oncology, University of British Columbia, Vancouver, Canada
    Competing interests
    No competing interests declared.
  12. Manolis Fanto

    Department of Basic and Clinical Neuroscience, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  13. Per Stenberg

    Department of Molecular Biology, Umeå University, Umeå, Sweden
    Competing interests
    No competing interests declared.
  14. Mattias Mannervik

    Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden
    For correspondence
    mattias.mannervik@su.se
    Competing interests
    No competing interests declared.
  15. Helen McNeill

    Department of Molecular Genetics, University of Toronto, Toronto, Canada
    For correspondence
    mcneill@lunenfeld.ca
    Competing interests
    Helen McNeill, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1126-5154

Funding

Canadian Institutes of Health Research (FDN 143319)

  • Helen McNeill

Medical Research Council (NIRG-G1002186)

  • Manolis Fanto

Knut och Alice Wallenbergs Stiftelse

  • Per Stenberg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Publication history

  1. Received: November 8, 2016
  2. Accepted: March 15, 2017
  3. Accepted Manuscript published: March 22, 2017 (version 1)
  4. Version of Record published: April 28, 2017 (version 2)

Copyright

© 2017, Yeung et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,321
    Page views
  • 361
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kelvin Yeung
  2. Ann Boija
  3. Edvin Karlsson
  4. Per-Henrik Holmqvist
  5. Yonit Tsatskis
  6. Ilaria Nisoli
  7. Damian B Yap
  8. Alireza Lorzadeh
  9. Michelle Moksa
  10. Martin Hirst
  11. Samuel Aparicio
  12. Manolis Fanto
  13. Per Stenberg
  14. Mattias Mannervik
  15. Helen McNeill
(2017)
Atrophin controls developmental signaling pathways via interactions with Trithorax-like
eLife 6:e23084.
https://doi.org/10.7554/eLife.23084