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

Giulia Cova (), Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann and Stefan Mundlos ()
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Giulia Cova: RG Development & Disease
Juliane Glaser: RG Development & Disease
Robert Schöpflin: RG Development & Disease
Cesar Augusto Prada-Medina: RG Development & Disease
Salaheddine Ali: RG Development & Disease
Martin Franke: RG Development & Disease
Rita Falcone: RG Development & Disease
Miriam Federer: RG Development & Disease
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
Stefan Mundlos: RG Development & Disease

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37057-z

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