Molecular basis of CTCF binding polarity in genome folding

Elphège P. Nora (), Laura Caccianini, Geoffrey Fudenberg, Kevin So, Vasumathi Kameswaran, Abigail Nagle, Alec Uebersohn, Bassam Hajj, Agnès Le Saux, Antoine Coulon, Leonid A. Mirny, Katherine S. Pollard, Maxime Dahan and Benoit G. Bruneau ()
Additional contact information
Elphège P. Nora: Gladstone Institutes
Laura Caccianini: Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168
Geoffrey Fudenberg: Gladstone Institutes
Kevin So: Gladstone Institutes
Vasumathi Kameswaran: Gladstone Institutes
Abigail Nagle: Gladstone Institutes
Alec Uebersohn: Gladstone Institutes
Bassam Hajj: Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168
Agnès Le Saux: Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Mammalian Developmental Epigenetics group
Antoine Coulon: Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168
Leonid A. Mirny: Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology
Katherine S. Pollard: Gladstone Institutes
Maxime Dahan: Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168
Benoit G. Bruneau: Gladstone Institutes

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Current models propose that boundaries of mammalian topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize loops, the molecular basis of this polarity remains unclear. By combining ChIP-seq and single molecule live imaging we report that CTCF positions cohesin, but does not control its overall binding dynamics on chromatin. Using an inducible complementation system, we find that CTCF mutants lacking the N-terminus cannot insulate TADs properly. Cohesin remains at CTCF sites in this mutant, albeit with reduced enrichment. Given the orientation of CTCF motifs presents the N-terminus towards cohesin as it translocates from the interior of TADs, these observations explain how the orientation of CTCF binding sites translates into genome folding patterns.

Date: 2020
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DOI: 10.1038/s41467-020-19283-x

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