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Preprint

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3

MPG-Autoren
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Cova,  Giulia
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Glaser,  Juliane
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Schöpflin,  Robert
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Ali,  Salaheddine
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Prada-Medina,  César A.
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Franke,  Martin
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Falcone,  Rita
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Federer,  Miriam
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Wittler,  Lars
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Timmermann,  Bernd
Sequencing Core Facility (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Spielmann,  Malte
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos,  Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Cova et al_2022.pdf
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Zitation

Cova, G., Glaser, J., Schöpflin, R., Ali, S., Prada-Medina, C. A., Franke, M., et al. (2022). Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3. bioRxiv (Preprint Server). doi:10.1101/2022.02.09.479724.


Zitierlink: https://hdl.handle.net/21.11116/0000-000A-29C7-8
Zusammenfassung
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 investigated 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 resulted in restructuring of the chromatin architecture. This led to an ectopic activation
of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern. Artificial
repositioning of the AER-specific enhancers of Fgf8 was sufficient to induce misexpression of
Lbx1 and Btrc. We provide evidence that the SHFM3 phenotype is the result of a combinatorial
effect on gene misexpression and dosage in the developing limb. Our results reveal new
insights into the molecular mechanism underlying SHFM3 and provide novel conceptual
framework for how genomic rearrangements can cause gene misexpression and disease.