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

Davidson, I. F.; Barth, R.; Zaczek, M.; van der Torre, J.; Tang, W.; Nagasaka, K.; Janissen, R.; Kerssemakers, J.; Wutz, G.; Dekker, C.; Peters, J.-M.

doi:10.1101/2022.09.08.507093

bioRxiv · 10.1101/2022.09.08.507093

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

Davidson, I. F.·Barth, R.·Zaczek, M.·van der Torre, J.·Tang, W.·Nagasaka, K.·Janissen, R.·Kerssemakers, J.·Wutz, G.·Dekker, C.·Peters, J.-M.

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Abstract

In eukaryotes, genomic DNA is extruded into loops by cohesin1. By restraining this process, the DNA-binding protein CTCF generates topologically associating domains (TADs)2-4 that play key roles in gene regulation and recombination during development and disease1,5-8. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unknown9. 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, as well as to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted, but unexpectedly is dependent on DNA tension. Moreover, CTCF regulates cohesins 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, where 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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Davidson, I. F., Barth, R., Zaczek, M., van der Torre, J., Tang, W., Nagasaka, K., Janissen, R., Kerssemakers, J., Wutz, G., Dekker, C., Peters, J.-M.. 2022-09-09. CTCF is a DNA-tension-dependent barrier to cohesin-mediated DNA loop extrusion. https://doi.org/10.1101/2022.09.08.507093

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