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Histone modifications at human enhancers reflect global cell-type-specific gene expression

Nature volume 459, pages 108–112 (2009)Cite this article

Abstract

The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene1,2,3, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome4,5,6. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.

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Figure 1: Chromatin modifications at promoters are generally cell-type-invariant whereas those at enhancers are cell-type-specific.
Figure 2: Genome-wide enhancer predictions in human cells.
Figure 3: Chromatin modifications at enhancers are globally related to cell-type-specific gene expression.
Figure 4: Chromatin modifications are associated with an increased regulatory response of transcription-factor-binding sites at enhancers.

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Gene Expression Omnibus

Data deposits

Microarray data have been submitted to the GEO repository under accession numbers GSE14083, GSE8098, GSE7872 and GSE7118.

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Acknowledgements

We thank members of the Ren laboratory for comments. This work was supported by funding from American Cancer Society (R.D.H.), NIAID Intramural Research Program (V.V.L.), LICR (B.R.), NHGRI (B.R.), NCI (B.R.) and CIRM (B.R.).

Author Contributions R.D.H., N.D.H., G.C.H. and B.R. designed the experiments; R.D.H., N.D.H., L.F.H., Z.Y., L.K.L., R.K.S., C.W.C., H.L. and X.Z. conducted the ChIP-chip experiments; G.C.H. and K.A.C. analysed the ChIP-chip data; G.C.H. predicted enhancers; R.D.H. and L.K.L. conducted the reporter assays; J.E.A.-B., R.S. and J.A.T. provided human ES cells and expression data; V.V.L. provided advice and antibodies for CTCF-ChIP experiments; P.K., A.S. and M.K. analysed the transcription factor motifs; G.E.C. performed and analysed the DNaseI-chip experiments; and N.D.H., G.C.H., R.D.H. and B.R. wrote the manuscript.

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Author notes

  1. Nathaniel D. Heintzman, Gary C. Hon and R. David Hawkins: These authors contributed equally to this work.

Authors and Affiliations

  1. Ludwig Institute for Cancer Research,,

    Nathaniel D. Heintzman, Gary C. Hon, R. David Hawkins, Lindsey F. Harp, Zhen Ye, Leonard K. Lee, Rhona K. Stuart, Christina W. Ching, Keith A. Ching & Bing Ren

  2. Biomedical Sciences Graduate Program,,

    Nathaniel D. Heintzman

  3. Bioinformatics Program, and,,

    Gary C. Hon

  4. Department of Cellular and Molecular Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA,

    Bing Ren

  5. MIT Computer Science and Artificial Intelligence Laboratory, 32 Vassar Street, Cambridge, Massachusetts 02139, USA ,

    Pouya Kheradpour, Alexander Stark & Manolis Kellis

  6. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA ,

    Alexander Stark & Manolis Kellis

  7. Morgridge Institute for Research, Madison, Wisconsin 53707-7365, USA ,

    Jessica E. Antosiewicz-Bourget, Ron Stewart & James A. Thomson

  8. Roche NimbleGen, Inc., 500 South Rosa Road, Madison, Wisconsin 53719, USA ,

    Hui Liu, Xinmin Zhang & Roland D. Green

  9. National Institutes of Allergy and Infectious Disease, 5640 Fishers Lane, Rockville, Maryland 20852, USA ,

    Victor V. Lobanenkov

  10. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA ,

    James A. Thomson

  11. and Department of Pediatrics, Institute for Genome Sciences and Policy, Duke University, 101 Science Drive, Durham, North Carolina 27708, USA,

    Gregory E. Crawford

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  1. Nathaniel D. Heintzman
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Corresponding author

Correspondence to Bing Ren.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Data, Supplementary References, Supplementary Figures S1- S14 with Legends, Supplementary Table Captions S1-S16 and Supplementary Tables S1-S16 (PDF 6262 kb)

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Heintzman, N., Hon, G., Hawkins, R. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009). https://doi.org/10.1038/nature07829

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