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Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding

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Schöpflin,  Robert
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

Heinrich,  Verena
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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

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

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

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Haas,  Stefan
Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Vingron,  Martin
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), 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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Citation

Andrey, G., Schöpflin, R., Jerković, I., Heinrich, V., Ibrahim, D., Paliou, C., et al. (2017). Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding. Genome Research, 27(2), 223-233. doi:10.1101/gr.213066.116.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-3D5C-F
Abstract
Complex regulatory landscapes control the pleiotropic transcriptional activities of developmental genes. For most genes, the number, location and dynamic of their associated regulatory elements are unknown. In this work we characterized the three-dimensional chromatin micro-architecture and regulatory landscape of 446 limb-associated gene loci in mouse using Capture-C, ChIP-seq and RNA-seq in forelimb, hindlimb at three developmental stages and midbrain. The fine mapping of chromatin interactions revealed a strong preference for functional genomic regions such as repressed or active domains. By combining chromatin marks and interaction peaks, we annotated more than one thousand putative limb enhancers and their associated genes. Moreover, the analysis of chromatin interactions revealed two regimes of chromatin folding, one producing interactions stable across tissues and stages and another one associated with tissue and/or stage-specific interactions. Whereas stable interactions associate strongly with CTCF/RAD21 binding, the intensity of variable interactions correlates with changes in underlying chromatin modifications, specifically at the viewpoint and at the interaction site. In conclusion, this comprehensive dataset provides a resource for the characterization of hundreds of limb-associated regulatory landscapes and a framework to interpret the chromatin folding dynamics observed during embryogenesis.