Mammalian interphase chromosomes fold into a multitude of loops to fit the 
confines of cell nuclei, and looping is tightly linked to regulated function. 
Chromosome conformation capture (3C) technology has significantly advanced our 
understanding of this structure-to-function relationship. However, all 3C-based 
methods rely on chemical cross-linking to stabilize spatial interactions. This 
step remains a "black box" as regards the biases it may introduce, and some 
discrepancies between microscopy and 3C studies have now been reported. To 
address these concerns, we developed "i3C", a novel approach for capturing 
spatial interactions without a need for cross-linking. We apply i3C to intact 
nuclei of living cells and exploit native forces that stabilize chromatin 
folding. Using different cell types and loci, computational modeling, and a 
methylation-based orthogonal validation method, "TALE-iD", we show that native 
interactions resemble cross-linked ones, but display improved signal-to-noise 
ratios and are more focal on regulatory elements and CTCF sites, while strictly 
abiding to topologically associating domain restrictions.