PT  - JOURNAL ARTICLE
AU  - Anders S. Hansen
AU  - Assaf Amitai
AU  - Claudia Cattoglio
AU  - Robert Tjian
AU  - Xavier Darzacq
TI  - Guided nuclear exploration increases CTCF target search efficiency
AID  - 10.1101/495457
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 495457
4099  - http://biorxiv.org/content/early/2018/12/13/495457.short
4100  - http://biorxiv.org/content/early/2018/12/13/495457.full
AB  - Mammalian genomes are enormous. For a DNA-binding protein, this means that 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 in the nucleus in a manner that is largely dependent on its RNA-binding region (RBR). Integrating theory, we devise a new model, Anisotropic Diffusion through transient Trapping in Zones (ADTZ), to explain this. Functionally, transient RBR-mediated trapping increases the efficiency of CTCF target search by ∼2.5 fold. Since the RBR-domain also mediates CTCF clustering, 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 represent a general target search mechanism in mammalian cells.