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An oestrogen-receptor-α-bound human chromatin interactome

Abstract

Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally. Many transcription factors bind to regulatory DNA elements distant from gene promoters. Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor α (ER-α) in the human genome. We found that most high-confidence remote ER-α-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-α functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes.

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Figure 1: ChIA-PET method with validations.
Figure 2: ER-αBS reproducibility and association with chromatin interactions.
Figure 3: Association of ER-α-bound chromatin interactions with functional marks.
Figure 4: Proposed ER-α-bound chromatin interaction and transcription regulation mechanism.
Figure 5: ER-α-bound chromatin interactions are required for transcription activation.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The data in the ChIA-PET libraries have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE18046.

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Acknowledgements

The authors acknowledge the Genome Technology and Biology Group at the Genome Institute of Singapore for technical support; A. Shahab, C. C. Seng and F. H. Mulawadi for computing support; S. Luo and G. Schroth for Illumina sequencing support; and W. de Laat, B. Ren and X. S. Liu for advice. M.J.F., P.Y.H.H., Y.H., P.Y.T. and Y.K.L. are supported by A*STAR Scholarships. M.J.F. is supported by a L’Oreal-UNESCO For Women In Science National Fellowship. Y.R. and C.L.W. are supported by A*STAR of Singapore and NIH ENCODE grants (R01 HG004456-01, R01HG003521-01 and part of 1U54HG004557-01).

Author Contributions M.J.F. and Y.R. conceptualized the ChIA-PET strategy. M.J.F., E.C. and Y.R. designed the experiments. M.J.F., M.H.L., Y.F.P., J.L., A.H., P.H.M., E.G.Y.C., P.Y.Y.H., W.-J.W., Y.H., Y.L., P.Y.T., P.Y.C., K.D.S.A.W., B.Z., K.S.L., S.C.L., J.S.Y., R.J., K.V.D., J.S.T., Y.K.L., T.H., H.G.S., X.R. and V.C.-R. performed experiments. M.J.F., X.H., Y.B.M., Y.L.O., S.V., H.-S.O., P.N.A., V.B.V., Y.K.L., R.K.M.K., G.B., H.G.S., X.R., V.C.-R., W-K.S., C.-L.W., E.C. and Y.R. analysed experimental data. E.T.L., E.C. and C.-L.W. commented on the manuscript drafts; M.J.F. and Y.R. wrote the paper.

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Correspondence to Edwin Cheung or Yijun Ruan.

Supplementary information

Supplementary Information

This file contains Supplementary Results, Supplementary Methods, Supplementary Notes, Supplementary Tables 4-7 and 9 (see separate files s2-s6 for Supplementary Tables 1-3, 8 and 10), Supplementary Figures 1-21 with Legends, Supplementary References and a Supplementary Glossary. (PDF 16985 kb)

Supplementary Table 1

This file shows all ERα binding sites found by ChIA-PET and supporting datasets, and associated genes. (XLS 3861 kb)

Supplementary Table 2

This file shows all raw interchromosomal and intrachromosomal inter-ligation PET clusters (duplex interactions) found by ChIA-PET experiments. (XLS 1763 kb)

Supplementary Table 3

This file shows processed interaction regions found by ChIA-PET experiments, and associated genes. (XLS 915 kb)

Supplementary Table 8

This file shows loop, anchor and enclosed anchor genes from ChIA-PET experiments, and their transcriptional characteristics. (XLS 2688 kb)

Supplementary Table 10

This file shows sequence and technical information used in the ChIA-PET and validation experiments. (XLS 43 kb)

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Fullwood, M., Liu, M., Pan, Y. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64 (2009). https://doi.org/10.1038/nature08497

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