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

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.

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 Creators:
Ringel, Alessa1, Author              
Szabo, Quentin , Author
Chiariello, Andrea M. , Author
Chudzik, Konrad1, Author              
Schöpflin, Robert1, Author              
Rothe, Patricia 1, Author
Mattei, Alexandra L.2, Author              
Zehnder, Tobias3, Author              
Harnett, Dermot , Author
Laupert, Verena3, Author              
Bianco, Simona, Author
Hetzel, Sara2, Author              
Phan, Mai1, Author              
Schindler, Magdalena1, Author              
Ibrahim, Daniel M.1, Author              
Paliou, Christina1, Author              
Esposito, Andrea, Author
Prada-Medina, Cesar A. , Author
Haas, Stefan4, Author              
Giere, Peter , Author
Vingron, Martin3, Author              Wittler, Lars5, Author              Meissner, Alexander2, Author              Nicodemi, Mario , AuthorCavalli, Giacomo , AuthorBantignies, Frédéric , AuthorMundlos, Stefan1, Author              Robson, Michael1, Author               more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
3Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
4Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
5Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              

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Free keywords: Topologically-associating domains, TADs, lamina-associated domain, enhancer-promoter specificity, DNA methylation, gene regulation, development, loop extrusion, 3D genome organisation
 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.

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Language(s): eng - English
 Dates: 2021-10-09
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2021.10.08.463672
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Title: bioRxiv
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