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Enhancer-promoter interactions form independently of genomic distance and are functional across TAD boundaries

Pedro Borges Pinto, Alexia Grasso, Deevitha Balasubramanian, Séverine Vincent, Hélène Tarayre, Damien Lajoignie, View ORCID ProfileYad Ghavi-Helm
doi: https://doi.org/10.1101/2022.08.29.505755
Pedro Borges Pinto
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
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Alexia Grasso
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
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Deevitha Balasubramanian
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
2Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Opposite Sree Rama Engineering College, Rami Reddy Nagar, Mangalam, Tirupati, Andhra Pradesh, India; Pin - 517507
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Séverine Vincent
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
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Hélène Tarayre
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
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Damien Lajoignie
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
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Yad Ghavi-Helm
1Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, 46 allée d’Italie F-69364 Lyon, France
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  • ORCID record for Yad Ghavi-Helm
  • For correspondence: yad.ghavi-helm@ens-lyon.fr
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Abstract

Developmental enhancers are essential regulatory elements that drive precise spatio-temporal gene expression patterns. They do so by interacting with the promoter of their target genes, often across large genomic distances, in a highly specific manner. However, it is unclear how such specificity can be achieved. While several studies have suggested that Topologically Associating Domains (TADs)1–3 facilitate and constrain enhancer-promoter interactions, the role of TAD boundaries in effectively restricting enhancer-promoter interactions is heavily debated. Here we show that enhancers can establish long-range interactions across TAD boundaries and even between different chromosomes. Moreover, some of these interactions are functional in vivo, illustrating their functional importance. Using the twist locus in Drosophila embryos, we systematically relocated one of its enhancers to different regulatory contexts and distances from the twist promoter. We found that the twist promoter can engage in functional enhancer-promoter interactions across a TAD boundary and that distal interactions are sometimes favored over proximal ones. Our results demonstrate that TAD boundaries are not sufficient to constrain enhancer-promoter interactions and that the formation of long-range interactions is not solely driven by distance. These observations suggest that other general mechanisms must exist to establish and maintain specific enhancer-promoter interactions across large distances.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 29, 2022.
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Enhancer-promoter interactions form independently of genomic distance and are functional across TAD boundaries
Pedro Borges Pinto, Alexia Grasso, Deevitha Balasubramanian, Séverine Vincent, Hélène Tarayre, Damien Lajoignie, Yad Ghavi-Helm
bioRxiv 2022.08.29.505755; doi: https://doi.org/10.1101/2022.08.29.505755
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Enhancer-promoter interactions form independently of genomic distance and are functional across TAD boundaries
Pedro Borges Pinto, Alexia Grasso, Deevitha Balasubramanian, Séverine Vincent, Hélène Tarayre, Damien Lajoignie, Yad Ghavi-Helm
bioRxiv 2022.08.29.505755; doi: https://doi.org/10.1101/2022.08.29.505755

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