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; Stefan Mundlos

doi:10.1038/s41467-023-37057-z

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, Stefan Mundlos^*

^*Corresponding author for this work

Institute of Human Genetics

19 Citations (Scopus)

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.

Original language	English
Article number	1475
Journal	Nature Communications
Volume	14
Issue number	1
Pages (from-to)	1475
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-023-37057-z
Publication status	Published - 17.03.2023

Funding

This study was supported by grants from the Deutsche Forschungsgemeinschaft (MU 880/16-1, MU 880/20-1) to S.M. We thank the transgenic unit, sequencing core and animal facility of Max Planck Institute for Molecular Genetics for technical assistance, Ute Fischer for technical support and Norbert Brieske for help with whole mount in situ hybridizations and image processing. We would like to thank all members of the Mundlos laboratory and Tugce Aktas for continuous support and discussion. We would like to particularly thank Dario Lupiáñez, Chiara Anania, Lila Allou and Jane Skok for critical reading of the manuscript.

Research Areas and Centers

Research Area: Medical Genetics
Centers: Center for Rare Diseases (ZSE)

DFG Research Classification Scheme

2.22-03 Human Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-023-37057-z

Cite this

Cova, G., Glaser, J., Schöpflin, R., Prada-Medina, C. A., Ali, S., Franke, M., Falcone, R., Federer, M., Ponzi, E., Ficarella, R., Novara, F., Wittler, L., Timmermann, B., Gentile, M., Zuffardi, O., Spielmann, M., & Mundlos, S. (2023). Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3. Nature Communications, 14(1), 1475. Article 1475. https://doi.org/10.1038/s41467-023-37057-z

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

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.",

author = "Giulia Cova and Juliane Glaser and Robert Sch{\"o}pflin and Prada-Medina, \{Cesar Augusto\} and Salaheddine Ali and Martin Franke and Rita Falcone and Miriam Federer and Emanuela Ponzi and Romina Ficarella and Francesca Novara and Lars Wittler and Bernd Timmermann and Mattia Gentile and Orsetta Zuffardi and Malte Spielmann and Stefan Mundlos",

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doi = "10.1038/s41467-023-37057-z",

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Cova, G, Glaser, J, Schöpflin, R, Prada-Medina, CA, Ali, S, Franke, M, Falcone, R, Federer, M, Ponzi, E, Ficarella, R, Novara, F, Wittler, L, Timmermann, B, Gentile, M, Zuffardi, O, Spielmann, M & Mundlos, S 2023, 'Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3', Nature Communications, vol. 14, no. 1, 1475, pp. 1475. https://doi.org/10.1038/s41467-023-37057-z

TY - JOUR

T1 - Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3

AU - Cova, Giulia

AU - Glaser, Juliane

AU - Schöpflin, Robert

AU - Prada-Medina, Cesar Augusto

AU - Ali, Salaheddine

AU - Franke, Martin

AU - Falcone, Rita

AU - Federer, Miriam

AU - Ponzi, Emanuela

AU - Ficarella, Romina

AU - Novara, Francesca

AU - Wittler, Lars

AU - Timmermann, Bernd

AU - Gentile, Mattia

AU - Zuffardi, Orsetta

AU - Spielmann, Malte

AU - Mundlos, Stefan

PY - 2023/3/17

Y1 - 2023/3/17

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-37057-z

M3 - Journal articles

C2 - 36928426

AN - SCOPUS:85150665876

SN - 1751-8628

VL - 14

SP - 1475

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1475

ER -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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