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ChIP-seq accurately predicts tissue-specific activity of enhancers

Nature volume 457, pages 854–858 (2009)Cite this article

Abstract

A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.

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Figure 1: Tissue dissection boundaries, overview of the ChIP-seq approach and summary of p300 results.
Figure 2: p300 binding accurately predicts enhancers and their tissue-specific activity patterns.
Figure 3: Examples of successful prediction of in vivo enhancers by p300 binding in embryonic tissues.
Figure 4: In all tissues examined, p300 is enriched at highly conserved non-coding regions.
Figure 5: p300 peaks are enriched near genes that are expressed in the same tissue.

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Primary accessions

Gene Expression Omnibus

Data deposits

All ChIP-seq data sets described in this study have been deposited at the National Center for Biotechnology Information (NCBI) in the Gene Expression Omnibus (GEO) database under accession number GSE13845.

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Acknowledgements

We wish to thank R. Hosseini and S. Phouanenavong for technical support, and J. Rubenstein, J. Long, J. Choi and Y. Zhu for help with microarray experiments. This work was performed under the auspices of the US Department of Energy’s Office of Science, Biological and Environmental Research Program and by the University of California, Lawrence Berkeley National Laboratory under contract no. DE-AC02-05CH11231, Lawrence Livermore National Laboratory under contract no. DE-AC52-07NA27344, and Los Alamos National Laboratory under contract no. DE-AC02-06NA25396. L.A.P. and E.M.R. were supported by the Berkeley-PGA, under the Programs for Genomic Applications, funded by National Heart, Lung, & Blood Institute, and L.A.P. by the National Human Genome Research Institute. A.V. was supported by an American Heart Association postdoctoral fellowship. B.R. was supported by grants from the National Human Genome Research Institute and the Ludwig Institute for Cancer Research.

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Author notes

  1. Axel Visel and Matthew J. Blow: These authors contributed equally to this work.

Authors and Affiliations

  1. Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA,

    Axel Visel, Matthew J. Blow, Jennifer A. Akiyama, Amy Holt, Ingrid Plajzer-Frick, Malak Shoukry, Veena Afzal, Edward M. Rubin & Len A. Pennacchio

  2. US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA,

    Matthew J. Blow, Tao Zhang, Crystal Wright, Feng Chen, Edward M. Rubin & Len A. Pennacchio

  3. Ludwig Institute for Cancer Research, University of California San Diego (UCSD) School of Medicine, La Jolla, California 92093, USA ,

    Zirong Li & Bing Ren

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Correspondence to Len A. Pennacchio.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-6 with Legends and Supplementary Tables 1, 6 and 7. (PDF 1271 kb)

Supplementary Tables

This file contains Supplementary Tables 2-4 which show p300 peaks in forebrain, midbrain, and limb (XLS 472 kb)

Supplementary Tables

This file contains Supplementary Table 5 which shows results of in vivo enhancer assays in transgenic mice (XLS 85 kb)

Supplementary Tables

This file contains Supplementary Tables 8-11 which show forebrain and limb over- and underexpressed genes (XLS 772 kb)

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Visel, A., Blow, M., Li, Z. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009). https://doi.org/10.1038/nature07730

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