Nature Communications (Apr 2023)
Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation
- 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-Konstantin Klever,
- Aybuge Altay,
- Pedro Vallecillo-García,
- Giovanna Carpentieri,
- Massimo Delledonne,
- Melanie-Jasmin Ort,
- Marko Schwestka,
- Giovanni Battista Ferrero,
- Marco Tartaglia,
- Alfredo Brusco,
- Manfred Gossen,
- Dirk Strunk,
- Sven Geißler,
- Stefan Mundlos,
- Sigmar Stricker,
- Petra Knaus,
- Elisa Giorgio,
- Malte Spielmann
Affiliations
- Uirá Souto Melo
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Jerome Jatzlau
- Freie Universität Berlin, Institute for Chemistry and Biochemistry
- Cesar A. Prada-Medina
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Elisabetta Flex
- Istituto Superiore di Sanità, Department of Oncology and Molecular Medicine
- Sunhild Hartmann
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Salaheddine Ali
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Robert Schöpflin
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Laura Bernardini
- Cytogenetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS
- Andrea Ciolfi
- Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS
- M-Hossein Moeinzadeh
- Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology
- Marius-Konstantin Klever
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Aybuge Altay
- Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology
- Pedro Vallecillo-García
- Freie Universität Berlin, Institute for Chemistry and Biochemistry
- Giovanna Carpentieri
- Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS
- Massimo Delledonne
- Department of Biotechnology, University of Verona
- Melanie-Jasmin Ort
- Freie Universität Berlin, Institute for Chemistry and Biochemistry
- Marko Schwestka
- Institute of Active Polymers, Helmholtz-Zentrum Hereon
- Giovanni Battista Ferrero
- Department of Clinical and Biological Sciences, University of Torino
- Marco Tartaglia
- Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS
- Alfredo Brusco
- Department of Medical Sciences, University of Torino
- Manfred Gossen
- Institute of Active Polymers, Helmholtz-Zentrum Hereon
- Dirk Strunk
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU)
- Sven Geißler
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité – Universitätsmedizin Berlin
- Stefan Mundlos
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- Sigmar Stricker
- Freie Universität Berlin, Institute for Chemistry and Biochemistry
- Petra Knaus
- Freie Universität Berlin, Institute for Chemistry and Biochemistry
- Elisa Giorgio
- Department of Molecular Medicine, University of Pavia
- Malte Spielmann
- Max Planck Institute for Molecular Genetics, Development and Disease Group
- DOI
- https://doi.org/10.1038/s41467-023-37585-8
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 13
Abstract
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.
