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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3

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Listed:
  • Giulia Cova

    (RG Development & Disease
    Charité Universitätsmedizin Berlin
    New York University School of Medicine, Langone Health Medical Center)

  • Juliane Glaser

    (RG Development & Disease)

  • Robert Schöpflin

    (RG Development & Disease
    Charité Universitätsmedizin Berlin
    Max Planck Institute for Molecular Genetics)

  • Cesar Augusto Prada-Medina

    (RG Development & Disease
    University of Oxford)

  • Salaheddine Ali

    (RG Development & Disease
    Charité Universitätsmedizin Berlin)

  • Martin Franke

    (RG Development & Disease
    Charité Universitätsmedizin Berlin
    Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide)

  • Rita Falcone

    (RG Development & Disease)

  • Miriam Federer

    (RG Development & Disease
    Universität Innsbruck)

  • Emanuela Ponzi

    (Medical Genetics Unit, Department of Reproductive Medicine, ASL Bari)

  • Romina Ficarella

    (Medical Genetics Unit, Department of Reproductive Medicine, ASL Bari)

  • Francesca Novara

    (Microgenomics Laboratory)

  • Lars Wittler

    (Max Planck Institute for Molecular Genetics)

  • Bernd Timmermann

    (Sequencing Core Facility, Max Planck Institute for Molecular Genetics)

  • Mattia Gentile

    (Medical Genetics Unit, Department of Reproductive Medicine, ASL Bari)

  • Orsetta Zuffardi

    (University of Pavia)

  • Malte Spielmann

    (Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität
    University of Lübeck
    Max Planck Institute for Molecular Genetics)

  • Stefan Mundlos

    (RG Development & Disease
    Charité Universitätsmedizin Berlin
    Charité Universitätsmedizin Berlin)

Abstract

Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.

Suggested Citation

  • Giulia Cova & Juliane Glaser & Robert Schöpflin & Cesar Augusto Prada-Medina & Salaheddine Ali & Martin Franke & Rita Falcone & Miriam Federer & Emanuela Ponzi & Romina Ficarella & Francesca Novara & , 2023. "Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37057-z
    DOI: 10.1038/s41467-023-37057-z
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