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 () and Malte Spielmann ()
Additional contact information
Uirá Souto Melo: Development and Disease Group
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
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
Marko Schwestka: Helmholtz-Zentrum Hereon
Giovanni Battista Ferrero: University of Torino
Marco Tartaglia: Ospedale Pediatrico Bambino Gesù, IRCCS
Alfredo Brusco: University of Torino
Manfred Gossen: Helmholtz-Zentrum Hereon
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
Stefan Mundlos: Development and Disease Group
Sigmar Stricker: Institute for Chemistry and Biochemistry
Petra Knaus: Institute for Chemistry and Biochemistry
Elisa Giorgio: University of Pavia
Malte Spielmann: Development and Disease Group

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-37585-8

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