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DNase I–hypersensitive exons colocalize with promoters and distal regulatory elements

Nature Genetics volume 45, pages 852–859 (2013)Cite this article

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Abstract

The precise splicing of genes confers an enormous transcriptional complexity to the human genome. The majority of gene splicing occurs cotranscriptionally, permitting epigenetic modifications to affect splicing outcomes. Here we show that select exonic regions are demarcated within the three-dimensional structure of the human genome. We identify a subset of exons that exhibit DNase I hypersensitivity and are accompanied by 'phantom' signals in chromatin immunoprecipitation and sequencing (ChIP-seq) that result from cross-linking with proximal promoter- or enhancer-bound factors. The capture of structural features by ChIP-seq is confirmed by chromatin interaction analysis that resolves local intragenic loops that fold exons close to cognate promoters while excluding intervening intronic sequences. These interactions of exons with promoters and enhancers are enriched for alternative splicing events, an effect reflected in cell type–specific periexonic DNase I hypersensitivity patterns. Collectively, our results connect local genome topography, chromatin structure and cis-regulatory landscapes with the generation of human transcriptional complexity by cotranscriptional splicing.

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Figure 1: A subset of exons exhibits DNase I hypersensitivity.
Figure 2: Combined ChIP-seq and ChIA-PET analysis shows that DHS exons interact with promoters and distal regulatory elements.
Figure 3: Schematic of local genome folding of exons within the SPTBN4 gene.
Figure 4: 3C validates cell type–specific interactions between exons and promoters.
Figure 5: Association between DHS exons and cell type–specific alternative splicing.

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Gene Expression Omnibus

Sequence Read Archive

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Acknowledgements

The authors would like to thank the following funding sources: the Australian National Health and Medical Research Council (Australia Fellowships 631668 to J.S.M., T.R.M. and M.B.C. and 631381 and 1021731 to S.L.E.); the Queensland State Government (National and International Research Alliance Program to L.K.N.); the National Breast Cancer Foundation Australia (to S.L.E.); the National Human Genome Research Institute (NHGRI; ENCODE grant HG004456 to Y.R., G.L. and K.S.S.); and the US National Institutes of Health (NHGRI ENCODE grants U54HG004592 and U54HG007599 to J.A.S.).

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Authors and Affiliations

  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia

    Tim R Mercer & Michael B Clark

  2. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, Queensland, Australia

    Tim R Mercer & Lars K Nielsen

  3. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia

    Stacey L Edwards

  4. SE Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    Stacey L Edwards

  5. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA

    Shane J Neph, Hao Wang, Andrew B Stergachis, Sam John, Richard Sandstrom & John A Stamatoyannopoulos

  6. Genome Institute of Singapore, Singapore

    Guoliang Li, Kuljeet S Sandhu & Yijun Ruan

  7. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    John S Mattick

  8. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia

    John S Mattick

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Contributions

T.R.M., G.L. and S.J.N. performed bioinformatic analysis. S.L.E. performed 3C analysis. G.L., K.S.S. and Y.R. performed ChIA-PET analysis. A.B.S., H.W., S.J. and R.S. performed native ChIP-seq and whole-genome sequencing. T.R.M., S.J.N., M.B.C., L.K.N., Y.R., J.S.M. and J.A.S. prepared the manuscript.

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Correspondence to John S Mattick or John A Stamatoyannopoulos.

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Mercer, T., Edwards, S., Clark, M. et al. DNase I–hypersensitive exons colocalize with promoters and distal regulatory elements. Nat Genet 45, 852–859 (2013). https://doi.org/10.1038/ng.2677

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