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Preformed Chromatin Topology Assists Transcriptional Robustness of Shh during Limb Development

View ORCID ProfileChristina Paliou, View ORCID ProfilePhiline Guckelberger, Robert Schöpflin, Verena Heinrich, View ORCID ProfileAndrea Esposito, View ORCID ProfileAndrea M. Chiariello, View ORCID ProfileSimona Bianco, Carlo Annunziatella, View ORCID ProfileJohannes Helmuth, View ORCID ProfileStefan Haas, View ORCID ProfileIvana Jerković, Norbert Brieske, Lars Wittler, Bernd Timmermann, View ORCID ProfileMario Nicodemi, View ORCID ProfileMartin Vingron, View ORCID ProfileStefan Mundlos, View ORCID ProfileGuillaume Andrey
doi: https://doi.org/10.1101/528877
Christina Paliou
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
2Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
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  • ORCID record for Christina Paliou
Philine Guckelberger
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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  • ORCID record for Philine Guckelberger
Robert Schöpflin
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Verena Heinrich
3Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Andrea Esposito
4Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
5Berlin Institute of Health (BIH), MDC-Berlin, 13125 Berlin, Germany
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Andrea M. Chiariello
4Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Simona Bianco
4Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Carlo Annunziatella
4Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Johannes Helmuth
6Otto-Warburg-Laboratory: Epigenomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
7Labor Berlin - Charité Vivantes, Humangenetik, 13353 Berlin, Germany
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Stefan Haas
3Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Ivana Jerković
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
8Institute of Human Genetics (IGH), 34396 Montpellier, France
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Norbert Brieske
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Lars Wittler
9Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Bernd Timmermann
10Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 Berlin, Germany
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Mario Nicodemi
4Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
5Berlin Institute of Health (BIH), MDC-Berlin, 13125 Berlin, Germany
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Martin Vingron
3Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Stefan Mundlos
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
2Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
11Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
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  • For correspondence: mundlos@molgen.mpg.de guillaume.andrey@unige.ch
Guillaume Andrey
1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
2Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
12Department of Genetic Medicine and Development, University of Geneva, 1205 Geneva, Switzerland
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  • For correspondence: mundlos@molgen.mpg.de guillaume.andrey@unige.ch
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Abstract

Long-range gene regulation involves physical proximity between enhancers and promoters to generate precise patterns of gene expression in space and time. However, in some cases proximity coincides with gene activation, whereas in others preformed topologies already exist before activation. In this study, we investigate the preformed configuration underlying the regulation of the Shh gene by its unique limb enhancer, the ZRS, in vivo during mouse development. Abrogating the constitutive transcription covering the ZRS region led to a shift within the Shh-ZRS contacts and a moderate reduction in Shh transcription. Deletion of the CTCF binding sites around the ZRS resulted in a loss of the Shh-ZRS preformed interaction and a 50% decrease in Shh expression but no phenotype, suggesting an additional, CTCF-independent mechanism of promoter-enhancer communication. This residual activity, however, was diminished by combining the loss of CTCF binding with a hypomorphic ZRS allele resulting in severe Shh loss-of-function and digit agenesis. Our results indicate that the preformed chromatin structure of the Shh locus is sustained by multiple components and acts to reinforce enhancer-promoter communication for robust transcription.

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Posted January 23, 2019.
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Preformed Chromatin Topology Assists Transcriptional Robustness of Shh during Limb Development
Christina Paliou, Philine Guckelberger, Robert Schöpflin, Verena Heinrich, Andrea Esposito, Andrea M. Chiariello, Simona Bianco, Carlo Annunziatella, Johannes Helmuth, Stefan Haas, Ivana Jerković, Norbert Brieske, Lars Wittler, Bernd Timmermann, Mario Nicodemi, Martin Vingron, Stefan Mundlos, Guillaume Andrey
bioRxiv 528877; doi: https://doi.org/10.1101/528877
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Preformed Chromatin Topology Assists Transcriptional Robustness of Shh during Limb Development
Christina Paliou, Philine Guckelberger, Robert Schöpflin, Verena Heinrich, Andrea Esposito, Andrea M. Chiariello, Simona Bianco, Carlo Annunziatella, Johannes Helmuth, Stefan Haas, Ivana Jerković, Norbert Brieske, Lars Wittler, Bernd Timmermann, Mario Nicodemi, Martin Vingron, Stefan Mundlos, Guillaume Andrey
bioRxiv 528877; doi: https://doi.org/10.1101/528877

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