Footprint-C reveals transcription factor modes in local clusters and long-range chromatin interactions.

The proximity ligation-based Hi-C and derivative methods are the mainstream tools to study genome-wide chromatin interactions. These methods often fragment the genome using enzymes functionally irrelevant to the interactions per se, restraining the efficiency in identifying structural features and the underlying regulatory elements. Here we present Footprint-C, which yields high-resolution chromatin contact maps built upon intact and genuine footprints protected by transcription factor (TF) binding. When analyzed at one-dimensional level, the billions of chromatin contacts from Footprint-C enable genome-wide analysis at single footprint resolution, and reveal preferential modes of local TF co-occupancy. At pairwise contact level, Footprint-C exhibits higher efficiency in identifying chromatin structural features when compared with other Hi-C methods, segregates chromatin interactions emanating from adjacent TF footprints, and uncovers multiway interactions involving different TFs. Altogether, Footprint-C results suggest that rich regulatory modes of TF may underlie both local residence and distal chromatin interactions, in terms of TF identity, valency, and conformational configuration.