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Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes

Nature Methods volume 12, pages 71–78 (2015)Cite this article

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Abstract

High-throughput methods based on chromosome conformation capture have greatly advanced our understanding of the three-dimensional (3D) organization of genomes but are limited in resolution by their reliance on restriction enzymes. Here we describe a method called DNase Hi-C for comprehensively mapping global chromatin contacts. DNase Hi-C uses DNase I for chromatin fragmentation, leading to greatly improved efficiency and resolution over that of Hi-C. Coupling this method with DNA-capture technology provides a high-throughput approach for targeted mapping of fine-scale chromatin architecture. We applied targeted DNase Hi-C to characterize the 3D organization of 998 large intergenic noncoding RNA (lincRNA) promoters in two human cell lines. Our results revealed that expression of lincRNAs is tightly controlled by complex mechanisms involving both super-enhancers and the Polycomb repressive complex. Our results provide the first glimpse of the cell type–specific 3D organization of lincRNA genes.

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Figure 1: Validation of DNase Hi-C.
Figure 2: Validation of targeted DNase Hi-C.
Figure 3: The intrachromosomal contact profile within 500 kb of the HOTAIR promoter in H1 and K562 cells.
Figure 4: Identification of lincRNA promoter–associated cis elements.
Figure 5: Characterization of contacts connecting lincRNA promoters to super-enhancers.

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Acknowledgements

We thank S. Fields and M. Groudine for critical reading of the manuscript. This work was supported by US National Institutes of Health grants R01 GM098039 (C.A.B.), GM046883 (C.M.D.) and R01 U41HG007000 (W.S.N.).

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Authors and Affiliations

  1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Wenxiu Ma, Ferhat Ay, Choli Lee, Gunhan Gulsoy, Jay Shendure & William S Noble

  2. Department of Pathology, University of Washington, Seattle, Washington, USA

    Xinxian Deng & Christine M Disteche

  3. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA

    Savannah Cook, Jennifer Hesson, Christopher Cavanaugh, Carol B Ware, Carl Anthony Blau & Zhijun Duan

  4. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA

    Savannah Cook, Jennifer Hesson, Christopher Cavanaugh & Carol B Ware

  5. Department of Radiation Oncology, University of Washington, Seattle, Washington, USA

    Anton Krumm

  6. Division of Hematology, University of Washington, Seattle, Washington, USA

    Carl Anthony Blau & Zhijun Duan

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  1. Wenxiu Ma
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Contributions

W.S.N., C.A.B., C.M.D., A.K. and Z.D. conceived of the project. Z.D. developed DNase Hi-C and targeted DNase Hi-C. Z.D., C.A.B, J.S., A.K., C.M.D., X.D., C.B.W. and W.S.N. designed experiments. Z.D., C.L., X.D., S.C., C.C. and J.H. performed experiments. W.M., F.A., G.G. and Z.D. analyzed experimental data under the supervision of W.S.N. W.S.N., J.S., C.A.B., C.M.D., A.K., W.M., F.A., X.D. and Z.D. wrote the paper.

Corresponding authors

Correspondence to William S Noble or Zhijun Duan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–17, Supplementary Tables 1–4, 6, 7, 11–15 and 24 and Supplementary Notes 1–6 (PDF 38883 kb)

Supplementary Table 5

The 220kb P-E library (XLS 59 kb)

Supplementary Table 8

List of contact partners identified by targeted DNase Hi-C P-E in H1 cells (XLSX 153 kb)

Supplementary Table 9

List of contact partners identified by targeted DNase Hi-C P-E in K562 cells (XLSX 175 kb)

Supplementary Table 10

The lincRNA P library (XLSX 182 kb)

Supplementary Table 16

List of contact partners identified by targeted DNase Hi-C incRNA in H1 cells (XLSX 1027 kb)

Supplementary Table 17

List of contact partners identified by targeted DNase Hi-C lincRNA in K562 cells (XLSX 781 kb)

Supplementary Table 18

Summary of enrichment analysis of Segway cis-elements (XLSX 18 kb)

Supplementary Table 19

Summary of enrichment analysis of DNase hypersensitive sites(DHSs) (XLSX 9 kb)

Supplementary Table 20

Summary of enrichment analysis of FAIRE-seq peaks (XLSX 9 kb)

Supplementary Table 21

Summary of enrichment analysis of super-enhancers (XLSX 174 kb)

Supplementary Table 22

Summary of enrichment analysis of TFBSs (XLSX 23 kb)

Supplementary Table 23

Adaptor and primer sequences (XLSX 12 kb)

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Ma, W., Ay, F., Lee, C. et al. Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes. Nat Methods 12, 71–78 (2015). https://doi.org/10.1038/nmeth.3205

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