Shared enhancer gene regulatory networks between wound and oncogenic programs

  1. Swann Floc'hlay
  2. Ramya Balaji
  3. Dimitrije Stanković
  4. Valerie M Christiaens
  5. Carmen Bravo González-Blas
  6. Seppe De Winter
  7. Gert J Hulselmans
  8. Maxime De Waegeneer
  9. Xiaojiang Quan
  10. Duygu Koldere
  11. Mardelle Atkins
  12. Georg Halder
  13. Mirka Uhlirova
  14. Anne Classen  Is a corresponding author
  15. Stein Aerts  Is a corresponding author
  1. VIB-KU Leuven Center for Brain and Disease Research, Belgium
  2. University of Freiburg, Germany
  3. University of Colognee, Germany
  4. KU Leuven, Belgium
  5. Sam Houston State University, United States
  6. VIB-KU Leuven Center for Cancer Biology, Belgium
  7. University of Cologne, Germany

Abstract

Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress and balance the activation of multiple programs including apoptosis, proliferation, and cell migration. Central to those responses are the activation of the JNK/MAPK and JAK/STAT signaling pathways. Yet, to what extent these signaling cascades interact at the cis-regulatory level, and how they orchestrate different regulatory and phenotypic responses is still unclear. Here, we aim to characterize the regulatory states that emerge and cooperate in the wound response, using the Drosophila melanogaster wing disc as a model system, and compare these with cancer cell states induced by rasV12scrib-/- in the eye disc. We used single-cell multiome profiling to derive enhancer Gene Regulatory Networks (eGRNs) by integrating chromatin accessibility and gene expression signals. We identify a 'proliferative' eGRN, active in the majority of wounded cells and controlled by AP-1 and STAT. In a smaller, but distinct population of wound cells, a 'senescent' eGRN is activated and driven by C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, and Vrille) and Scalloped. These two eGRN signatures are found to be active in tumor cells, at both gene expression and chromatin accessibility levels. Our single-cell multiome and eGRNs resource offers an in-depth characterisation of the senescence markers, together with a new perspective on the shared gene regulatory programs acting during wound response and oncogenesis.

Data availability

Single-cell sequencing data and aligned matrices have been deposited in GEO (accession code GSE205401)

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

Article and author information

Author details

  1. Swann Floc'hlay

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  2. Ramya Balaji

    Faculty of Biology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Dimitrije Stanković

    Institute for Genetics, University of Colognee, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Valerie M Christiaens

    Department of Human Genetics, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Carmen Bravo González-Blas

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Seppe De Winter

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7907-1247
  7. Gert J Hulselmans

    Department of Human Genetics, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  8. Maxime De Waegeneer

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  9. Xiaojiang Quan

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  10. Duygu Koldere

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  11. Mardelle Atkins

    Department of Biological Sciences, Sam Houston State University, Texas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0245-2452
  12. Georg Halder

    VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  13. Mirka Uhlirova

    Institute for Genetics, University of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5735-8287
  14. Anne Classen

    Faculty of Biology, University of Freiburg, Freiburg, Germany
    For correspondence
    anne.classen@zbsa.uni-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
  15. Stein Aerts

    VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
    For correspondence
    stein.aerts@kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8006-0315

Funding

European Research Council (724226_cisCONTROL)

  • Valerie M Christiaens
  • Gert J Hulselmans
  • Stein Aerts

Fonds Wetenschappelijk Onderzoek (G0C0417N)

  • Xiaojiang Quan
  • Duygu Koldere

Fonds Wetenschappelijk Onderzoek (G094121N)

  • Swann Floc'hlay

Deutsche Forschungsgemeinschaft (EXC-2189)

  • Anne Classen

Deutsche Forschungsgemeinschaft (CL490/3-1)

  • Anne Classen

Deutsche Forschungsgemeinschaft (EXC 2030)

  • Mirka Uhlirova

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

Copyright

© 2023, Floc'hlay 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.

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  1. Swann Floc'hlay
  2. Ramya Balaji
  3. Dimitrije Stanković
  4. Valerie M Christiaens
  5. Carmen Bravo González-Blas
  6. Seppe De Winter
  7. Gert J Hulselmans
  8. Maxime De Waegeneer
  9. Xiaojiang Quan
  10. Duygu Koldere
  11. Mardelle Atkins
  12. Georg Halder
  13. Mirka Uhlirova
  14. Anne Classen
  15. Stein Aerts
(2023)
Shared enhancer gene regulatory networks between wound and oncogenic programs
eLife 12:e81173.
https://doi.org/10.7554/eLife.81173

Share this article

https://doi.org/10.7554/eLife.81173

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