Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries

Li-Hsin Chang, Sourav Ghosh, Andrea Papale, Jennifer M. Luppino, Mélanie Miranda, Vincent Piras, Jéril Degrouard, Joanne Edouard, Mallory Poncelet, Nathan Lecouvreur, Sébastien Bloyer, Amélie Leforestier, Eric F. Joyce, David Holcman and Daan Noordermeer ()
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Li-Hsin Chang: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Sourav Ghosh: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Andrea Papale: Université PSL
Jennifer M. Luppino: University of Pennsylvania
Mélanie Miranda: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Vincent Piras: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Jéril Degrouard: Université Paris-Saclay, CNRS, Laboratoire de Physique des Solides (LPS)
Joanne Edouard: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Mallory Poncelet: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Nathan Lecouvreur: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Sébastien Bloyer: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Amélie Leforestier: Université Paris-Saclay, CNRS, Laboratoire de Physique des Solides (LPS)
Eric F. Joyce: University of Pennsylvania
David Holcman: Université PSL
Daan Noordermeer: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs.

Date: 2023
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DOI: 10.1038/s41467-023-41265-y

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