Zhang, Y.; Wu, Q.

CTCF architects 3D genome folding by anchoring or forestalling cohesin loop extrusion, but the exact mechanism remains obscure. Here, using clustered protocadherins (cPcdh) as model genes, we report that CTCF stabilizes or facilitates cohesin loop extrusion by enhancing its processivity. Specifically, we show that, compared with the Pcdh alpha and gamma clusters, the Pcdh beta cluster is greatly affected upon CTCF Y226A/F228A mutation in the N-terminal domain. Given the long-range distance of the Pcdh beta cluster from the distal enhancer, this finding has interesting implications in CTCF regulation of cohesin processivity along the linear chromatin during DNA loop extrusion. In particular, the effect on cohesin processivity upon CTCF Y226A/F228A mutation is conspicuously similar to that of WAPL overexpression, demonstrating that, contrary to the general view of blocking or forestalling cohesin, CTCF actually enhances or facilitates cohesin loop extrusion.