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 α and γ gene clusters, the Pcdhβ cluster is greatly affected upon CTCF^Y226A/F228A mutation in the N-terminal domain. Given the long-range distance of the Pcdhβ 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, suggesting that, in contrast to the general view of blocking or forestalling cohesin, CTCF may actually enhance or facilitate cohesin loop extrusion during 3D genome folding. We conclude that CTCF enhances cohesin enrichments via the N-terminal YDF motif in clustered protocadherin genes in a genomic-distance biased manner.