Guided nuclear exploration increases CTCF target search efficiency

The enormous size of mammalian genomes means that for a DNA-binding protein, the number of non-specific, off-target sites vastly exceeds the number of specific, cognate sites. How mammalian DNA-binding proteins overcome this challenge to efficiently locate their target sites is not known. Here through live-cell single-molecule tracking, we show that CCCTC-binding factor, CTCF, is repeatedly trapped in small zones that likely correspond to CTCF clusters, in a manner that is largely dependent on an internal RNA-binding region (RBR(i)). We develop a new theoretical model, Anisotropic Diffusion through transient Trapping in Zones (ADTZ), to explain CTCF dynamics. Functionally, transient RBR(i)-mediated trapping increases the efficiency of CTCF target search by ~2.5 fold. Overall, our results suggest a “guided” mechanism where CTCF clusters concentrate diffusing CTCF proteins near cognate binding sites, thus increasing the local ON-rate. We suggest that local guiding may allow DNA-binding proteins to more efficiently locate their target sites.