Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


A large number of cis-regulatory sequences have been annotated in the human genome1,2, but defining their target genes remains a challenge3. One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C)-based techniques4. 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 or activation of target genes by a ubiquitous transcription activator in a cell-specific manner.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Fine mapping of chromatin interactions in IMR90 cells.
Figure 2: Characterization of the IMR90 chromatin interactome.
Figure 3: Identification and characterization of promoter–enhancer interactions in IMR90 cells.
Figure 4: The higher order chromatin structure in IMR90 cells is stable during transient TNF-α signalling.

Accession codes


Gene Expression Omnibus

Data deposits

All sequencing data described in this study have been deposited to GEO under the accession number GSE43070. Some sequencing data used in this study were previously published and accession numbers can be found in Supplementary Methods. All chromatin interactions called in IMR90 cells can be found in Supplementary Data.


  1. The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012)

    Article  ADS  Google Scholar 

  2. Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012)

    Article  ADS  CAS  Google Scholar 

  3. Smallwood, A. & Ren, B. Genome organization and long-range regulation of gene expression by enhancers. Curr. Opin. Cell Biol. 25, 387–394 (2013)

    Article  CAS  Google Scholar 

  4. Dekker, J., Marti-Renom, M. A. & Mirny, L. A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nature Rev. Genet. 14, 390–403 (2013)

    Article  CAS  Google Scholar 

  5. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009)

    Article  ADS  CAS  Google Scholar 

  6. Imakaev, M. et al. Iterative correction of Hi-C data reveals hallmarks of chromosome organization. Nature Methods 9, 999–1003 (2012)

    Article  CAS  Google Scholar 

  7. de Wit, E. & de Laat, W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 26, 11–24 (2012)

    Article  CAS  Google Scholar 

  8. Mercer, T. R. et al. DNase I-hypersensitive exons colocalize with promoters and distal regulatory elements. Nature Genet. 45, 852–859 (2013)

    Article  CAS  Google Scholar 

  9. Noordermeer, D. et al. The dynamic architecture of Hox gene clusters. Science 334, 222–225 (2011)

    Article  ADS  CAS  Google Scholar 

  10. Lettice, L. A. et al. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA 99, 7548–7553 (2002)

    Article  ADS  CAS  Google Scholar 

  11. Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012)

    Article  CAS  Google Scholar 

  12. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012)

    Article  ADS  CAS  Google Scholar 

  13. Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012)

    Article  CAS  Google Scholar 

  14. Hawkins, R. D. et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 6, 479–491 (2010)

    Article  CAS  Google Scholar 

  15. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109–113 (2012)

    Article  ADS  CAS  Google Scholar 

  16. Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010)

    Article  ADS  CAS  Google Scholar 

  17. Hawkins, R. D. et al. Dynamic chromatin states in human ES cells reveal potential regulatory sequences and genes involved in pluripotency. Cell Res. 21, 1393–1409 (2011)

    Article  CAS  Google Scholar 

  18. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011)

    Article  ADS  CAS  Google Scholar 

  19. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010)

    Article  CAS  Google Scholar 

  20. Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013)

    Article  CAS  Google Scholar 

  21. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a polycomb group protein complex. Science 306, 1574–1577 (2004)

    Article  ADS  CAS  Google Scholar 

  22. Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012)

    Article  ADS  CAS  Google Scholar 

  23. Ong, C. T. & Corces, V. G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nature Rev. Genet. 12, 283–293 (2011)

    Article  CAS  Google Scholar 

  24. Schoenfelder, S., Clay, I. & Fraser, P. The transcriptional interactome: gene expression in 3D. Curr. Opin. Genet. Dev. 20, 127–133 (2010)

    Article  CAS  Google Scholar 

  25. Melo, C. A. et al. eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol. Cell 49, 524–535 (2013)

    Article  CAS  Google Scholar 

  26. Tan, P. Y. et al. Integration of regulatory networks by NKX3–1 promotes androgen-dependent prostate cancer survival. Mol. Cell. Biol. 32, 399–414 (2012)

    Article  CAS  Google Scholar 

  27. Jin, F., Li, Y., Ren, B. & Natarajan, R. P. U. 1 and C/EBP(alpha) synergistically program distinct response to NF-κB activation through establishing monocyte specific enhancers. Proc. Natl Acad. Sci. USA 108, 5290–5295 (2011)

    Article  ADS  CAS  Google Scholar 

  28. John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nature Genet. 43, 264–268 (2011)

    Article  CAS  Google Scholar 

  29. Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565–576 (2011)

    Article  CAS  Google Scholar 

  30. Jin, F., Li, Y., Ren, B. & Natarajan, R. Enhancers: multi-dimensional signal integrators. Transcription 2, 226–230 (2011)

    Article  CAS  Google Scholar 

Download references


We thank C. K. Glass for sharing the GRO-seq protocol, and S. Kuan and L. Edsall for assistance with high-throughput DNA sequencing and the initial processing. This work is supported by funds from the Ludwig Institute for Cancer Research, the California Institute of Regenerative Medicine (RN2-00905) and US National Institutes of Health (P50 GM085764-03 and U01 ES017166).

Author information

Authors and Affiliations



Y.L., F.J. and B.R. designed the studies. Y.L. conducted most of the experiments; F.J. carried out the data analysis; J.R.D., Z.Y., A.Y.L., C.Y., A.D.S. and C.E. contributed to the experiments; S.S. contributed to the data analysis; F.J., Y.L. and B.R. prepared the manuscript.

Corresponding author

Correspondence to Bing Ren.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Tables 1-6, Supplementary References and Supplementary Figures 1-24. (PDF 3678 kb)

Supplementary Data 1

This file contains data sheets of mapped cis-elements in IMR90 cells used in this study, including genomic locations of active TSS’s, inactive TSS’s, active enhancers, poised enhancers, CTCF peaks, H3K27me3 peaks and p65 peaks. (XLSX 5022 kb)

Supplementary Data 2

This file contains data sheets of chromatin interactions looping to the active promoters in IMR90 cells. The first sheet lists the locations of 11,313 anchors covering all active promoters in IMR90 cells. The second sheet lists the locations of all target peaks interacting with these anchors. (XLSX 3837 kb)

Supplementary Data 3

This zipped file contains a text file listing the locations of all 518,032 anchors covering every HindIII fragment in the human genome. Chromatin interactions were called for every one of these anchors. (ZIP 4820 kb)

Supplementary Data 4

This zipped file contains a text file listing the location of all 1,116,312 chromatin interactions identified in this study. (ZIP 19585 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jin, F., Li, Y., Dixon, J. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290–294 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing