A high-resolution map of the three-dimensional chromatin interactome in human cells

• Published in: Nature (London) 2013-11, Vol.503 (7475), p.290-294
• Main Authors: Jin, Fulai, Li, Yan, Dixon, Jesse R., Selvaraj, Siddarth, Ye, Zhen, Lee, Ah Young, Yen, Chia-An, Schmitt, Anthony D., Espinoza, Celso A., Ren, Bing
• Format: Article
• Language: English
• Subjects: 631/114/2114; 631/114/212/177; 631/337/100/101; 631/337/572/2102; Algorithms; Binding sites; Cell interaction; Cell Line; Chromatin; Chromatin - chemistry; Chromatin - genetics; Chromatin - metabolism; Chromosome Mapping; Cytogenetics; Data analysis; Enhancer Elements, Genetic - physiology; Experiments; Fibroblasts; Gene Expression Regulation; Genes; Genetic research; Genetic transcription; Genome, Human; Genomes; Humanities and Social Sciences; Humans; Imaging, Three-Dimensional; Interactomes; letter; Methods; multidisciplinary; Physiological aspects; Promoter Regions, Genetic - physiology; Protein Binding; RNA polymerase; Science; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12644

A novel approach to analyse high-depth Hi-C data provides a comprehensive chromatin interaction map at approximately 5–10 kb resolution in human fibroblasts; this reveals that TNF-α-responsive enhancers are already in contact with target promoters before signalling and that this chromatin looping is a strong predictor of gene induction. Chromatin interactions in human fibroblasts Hi-C is a genomic technology based on chromosome conformation capture (3C) that can identify long-range looping interactions of chromatin throughout the genome in an unbiased fashion. Bing Ren and colleagues have developed a novel analysis pipeline for Hi-C data sets that offers much improved resolution so that interactions between cis -regulatory elements such as enhancers and promoters can be defined. Applying it to study dynamic chromatin interactions during NF-κB signalling in human fibroblasts, they find that the majority of interactions between enhancers and promoters have already formed prior to the binding of sequence-specific transcription factors to enhancers. The regulatory targets of the transcription factor thus appear to have been hardwired into the chromatin architecture. A large number of cis -regulatory sequences have been annotated in the human genome 1 , 2 , but defining their target genes remains a challenge 3 . One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C)-based techniques 4 . However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C) 5 . We determined over one million long-range chromatin interactions at 5–10-kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter–enhancer contacts after TNF-α signalling in these cells. Unexpectedly, we found that TNF-α-responsive enhancers are already in contact with their target promoters before signalling. Such pre-existing chromatin looping, which also exists in other cell types with different extracellular signalling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is relatively stable and could influence the selection