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Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation

Author

Listed:
  • Uirá Souto Melo

    (Development and Disease Group
    Charité University Medicine Berlin)

  • Jerome Jatzlau

    (Institute for Chemistry and Biochemistry)

  • Cesar A. Prada-Medina

    (Development and Disease Group)

  • Elisabetta Flex

    (Department of Oncology and Molecular Medicine)

  • Sunhild Hartmann

    (Development and Disease Group)

  • Salaheddine Ali

    (Development and Disease Group)

  • Robert Schöpflin

    (Development and Disease Group)

  • Laura Bernardini

    (Casa Sollievo della Sofferenza Foundation, IRCCS)

  • Andrea Ciolfi

    (Ospedale Pediatrico Bambino Gesù, IRCCS)

  • M-Hossein Moeinzadeh

    (Department of Computational Molecular Biology)

  • Marius-Konstantin Klever

    (Development and Disease Group
    Charité University Medicine Berlin)

  • Aybuge Altay

    (Department of Computational Molecular Biology)

  • Pedro Vallecillo-García

    (Institute for Chemistry and Biochemistry)

  • Giovanna Carpentieri

    (Ospedale Pediatrico Bambino Gesù, IRCCS)

  • Massimo Delledonne

    (University of Verona)

  • Melanie-Jasmin Ort

    (Institute for Chemistry and Biochemistry
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin)

  • Marko Schwestka

    (Helmholtz-Zentrum Hereon
    Berlin-Brandenburg Center for Regenerative Therapies (BCRT))

  • Giovanni Battista Ferrero

    (University of Torino)

  • Marco Tartaglia

    (Ospedale Pediatrico Bambino Gesù, IRCCS)

  • Alfredo Brusco

    (University of Torino
    Città della Salute e della Scienza University Hospital)

  • Manfred Gossen

    (Helmholtz-Zentrum Hereon
    Berlin-Brandenburg Center for Regenerative Therapies (BCRT))

  • Dirk Strunk

    (Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU))

  • Sven Geißler

    (Berlin Institute of Health at Charité – Universitätsmedizin Berlin
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin
    Berlin-Brandenburg Center for Regenerative Therapies (BCRT))

  • Stefan Mundlos

    (Development and Disease Group
    Charité University Medicine Berlin)

  • Sigmar Stricker

    (Institute for Chemistry and Biochemistry)

  • Petra Knaus

    (Institute for Chemistry and Biochemistry)

  • Elisa Giorgio

    (University of Pavia
    IRCCS Mondino Foundation)

  • Malte Spielmann

    (Development and Disease Group
    University Hospitals Schleswig-Holstein, University of Lübeck and University of Kiel
    partner site Hamburg, Lübeck, Kiel)

Abstract

Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.

Suggested Citation

  • Uirá Souto Melo & Jerome Jatzlau & Cesar A. Prada-Medina & Elisabetta Flex & Sunhild Hartmann & Salaheddine Ali & Robert Schöpflin & Laura Bernardini & Andrea Ciolfi & M-Hossein Moeinzadeh & Marius-Ko, 2023. "Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37585-8
    DOI: 10.1038/s41467-023-37585-8
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    References listed on IDEAS

    as
    1. Martin Franke & Daniel M. Ibrahim & Guillaume Andrey & Wibke Schwarzer & Verena Heinrich & Robert Schöpflin & Katerina Kraft & Rieke Kempfer & Ivana Jerković & Wing-Lee Chan & Malte Spielmann & Bernd , 2016. "Formation of new chromatin domains determines pathogenicity of genomic duplications," Nature, Nature, vol. 538(7624), pages 265-269, October.
    2. Rebecca L. Eccles & Maciej T. Czajkowski & Carolin Barth & Paul Markus Müller & Erik McShane & Stephan Grunwald & Patrick Beaudette & Nora Mecklenburg & Rudolf Volkmer & Kerstin Zühlke & Gunnar Dittma, 2016. "Bimodal antagonism of PKA signalling by ARHGAP36," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

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