Genome-wide Analysis of Chromatin Interactions in Human Cells

Millions of cis-regulatory sequences have recently been found in the human genome, but the function of most cis-elements are not yet clear, in part due to the difficulty in determining their regulatory targets, which are often located millions of base pairs away and separated by one or more unrelated genes. To address this problem, the Hi-C method has been developed to identify long-range looping interactions in a genome-wide, unbiased fashion. However, current data analysis of Hi-C datasets cannot fully resolve regulatory interactions between enhancers and promoters due to the low resolution. Here, we generated a high-depth Hi-C dataset and applied a new analysis method that offers improved resolution permitting genome-wide identification of nearly one million chromatin interactions. We demonstrated the use of Hi-C to identify target promoters of enhancers regulated by NF-κB signaling and signal-dependent dynamic chromatin interaction at these enhancers in human cells. Surprisingly, our results showed that most NF-κB binding sites are looped to their regulatory targets prior to activation of the signaling pathway, and appear to undergo little change during signaling. This observation suggests that the chromatin organization landscape, once established in a cell type, is rather stable and may influence the selection and activation of target genes by a transcription factor.