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Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

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

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Chudzik,  Konrad
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;

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

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Mattei,  Alexandra L.
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Zehnder,  Tobias
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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

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Hetzel,  Sara
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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

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

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

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

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

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Vingron,  Martin
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), 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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Meissner,  Alexander
Dept. of Genome Regulation (Head: Alexander Meissner), 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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Robson,  Michael
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Ringel_2021.pdf
(Preprint), 10MB

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Citation

Ringel, A., Szabo, Q., Chiariello, A. M., Chudzik, K., Schöpflin, R., Rothe, P., et al. (2021). Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs. bioRxiv. doi:10.1101/2021.10.08.463672.


Cite as: https://hdl.handle.net/21.11116/0000-0009-8C09-0
Abstract
Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to
sample all enhancers located within the same topologically-associated domain (TAD). However,
many TADs contain multiple genes with divergent expression patterns, thereby indicating

additional forces further refine how enhancer activities are utilised. Here, we unravel the

mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient
Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a
strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment.
Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct
proximal enhancers that independently drive their expression. By contrast, in later embryonic

tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1
enhancers within the intact TAD. Combined, these features adapted an ancient regulatory

landscape during evolution to support two entirely independent Rex1 and Fat1 expression
programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory
landscapes can orchestrate complex divergent expression patterns in evolution.