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

Abstract

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.

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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

Accessions

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.

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Acknowledgements

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

Authors

Contributions

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.

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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)

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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). https://doi.org/10.1038/nature12644

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