This study presents a comprehensive high-resolution map of the three-dimensional chromatin interactome in human cells using Hi-C technology. The researchers identified over one million long-range chromatin interactions at a resolution of 5-10 kb, uncovering general principles of chromatin organization at various genomic features. They also characterized the dynamics of promoter-enhancer contacts in response to TNF-α signaling, finding that TNF-α responsive enhancers are already in contact with their target promoters before signaling. This pre-existing chromatin looping is a strong predictor of gene induction and suggests that the three-dimensional chromatin landscape is stable once established in a particular cell type. The study further reveals that the chromatin interactome map can improve the prediction of target genes of distal enhancers and provides insights into the regulation of gene expression by transcription factors. Overall, the findings highlight the importance of pre-existing chromatin looping in determining the spectrum of target genes for transcription factors in a cell type-specific manner.This study presents a comprehensive high-resolution map of the three-dimensional chromatin interactome in human cells using Hi-C technology. The researchers identified over one million long-range chromatin interactions at a resolution of 5-10 kb, uncovering general principles of chromatin organization at various genomic features. They also characterized the dynamics of promoter-enhancer contacts in response to TNF-α signaling, finding that TNF-α responsive enhancers are already in contact with their target promoters before signaling. This pre-existing chromatin looping is a strong predictor of gene induction and suggests that the three-dimensional chromatin landscape is stable once established in a particular cell type. The study further reveals that the chromatin interactome map can improve the prediction of target genes of distal enhancers and provides insights into the regulation of gene expression by transcription factors. Overall, the findings highlight the importance of pre-existing chromatin looping in determining the spectrum of target genes for transcription factors in a cell type-specific manner.