CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion

Iain F. Davidson, Roman Barth, Maciej Zaczek, Jaco Torre, Wen Tang, Kota Nagasaka, Richard Janissen, Jacob Kerssemakers, Gordana Wutz, Cees Dekker () and Jan-Michael Peters ()
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Iain F. Davidson: Vienna BioCenter
Roman Barth: Delft University of Technology
Maciej Zaczek: Vienna BioCenter
Jaco Torre: Delft University of Technology
Wen Tang: Vienna BioCenter
Kota Nagasaka: Vienna BioCenter
Richard Janissen: Delft University of Technology
Jacob Kerssemakers: Delft University of Technology
Gordana Wutz: Vienna BioCenter
Cees Dekker: Delft University of Technology
Jan-Michael Peters: Vienna BioCenter

Nature, 2023, vol. 616, issue 7958, 822-827

Abstract: Abstract In eukaryotes, genomic DNA is extruded into loops by cohesin1. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)2,3 that have important roles in gene regulation and recombination during development and disease1,4–7. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear8. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin’s loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.

Date: 2023
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DOI: 10.1038/s41586-023-05961-5

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