Title
CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion
Author
Davidson, Iain F. (Research Institute of Molecular Pathology, Vienna)
Barth, R. (TU Delft BN/Cees Dekker Lab; Kavli institute of nanoscience Delft)
Zaczek, Maciej (Research Institute of Molecular Pathology, Vienna)
van der Torre, J. (TU Delft BN/Cees Dekker Lab; Kavli institute of nanoscience Delft)
Tang, Wen (Research Institute of Molecular Pathology, Vienna)
Nagasaka, Kota (Research Institute of Molecular Pathology, Vienna)
Janissen, R. (TU Delft BN/Bionanoscience; Kavli institute of nanoscience Delft)
Kerssemakers, J.W.J. (TU Delft BN/Cees Dekker Lab; Kavli institute of nanoscience Delft)
Wutz, Gordana (Research Institute of Molecular Pathology, Vienna)
Dekker, C. (TU Delft BN/Cees Dekker Lab; Kavli institute of nanoscience Delft)
Peters, Jan Michael (Research Institute of Molecular Pathology, Vienna)
Department
BN/Bionanoscience
Date
2023
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.
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http://resolver.tudelft.nl/uuid:8a5844c1-360e-41bd-8d05-b5cbb7c5a3ad
DOI
https://doi.org/10.1038/s41586-023-05961-5
ISSN
0028-0836
Source
Nature: international weekly journal of science, 616 (7958), 822-827
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2023 Iain F. Davidson, R. Barth, Maciej Zaczek, J. van der Torre, Wen Tang, Kota Nagasaka, R. Janissen, J.W.J. Kerssemakers, Gordana Wutz, C. Dekker, Jan Michael Peters