CCCTC-binding Factor N-terminal Domain Regulates Clustered Protocadherin Gene Expression by Enhancing Cohesin Processivity

CTCF (CCCTC-binding factor) instructs 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 assists 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 CTCFY226A/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 CTCFY226A/F228A mutation is conspicuously similar to that of WAPL overexpression, suggesting that, in addition to the general view of blocking or forestalling cohesin, CTCF may also enhances or facilitates cohesin loop extrusion.