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

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.

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Cova, Giulia1, Author              
Glaser, Juliane1, Author              
Schöpflin, Robert1, Author              
Ali, Salaheddine1, Author              
Prada-Medina, César A.2, Author              
Franke, Martin1, Author              
Falcone, Rita 1, Author
Federer, Miriam 1, Author
Ponzi, Emanuela , Author
Ficarella, Romina , Author
Novara, Francesca , Author
Wittler, Lars3, Author              
Timmermann, Bernd4, Author              
Gentile, Mattia , Author
Zuffardi, Orsetta , Author
Spielmann, Malte2, Author              
Mundlos, Stefan1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              
3Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
4Sequencing Core Facility (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 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 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.

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Language(s): eng - English
 Dates: 2022-02-10
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2022.02.09.479724
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Title: bioRxiv (Preprint Server)
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