Histone modifications at human enhancers reflect global cell-type-specific gene expression (original) (raw)

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

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

References

1. Heintzman, N. D. & Ren, B. The gateway to transcription: identifying, characterizing and understanding promoters in the eukaryotic genome. Cell. Mol. Life Sci. 64, 386–400 (2007)
   Article CAS Google Scholar
2. Nightingale, K. P., O’Neill, L. P. & Turner, B. M. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr. Opin. Genet. Dev. 16, 125–136 (2006)
   Article CAS Google Scholar
3. Maston, G. A., Evans, S. K. & Green, M. R. Transcriptional regulatory elements in the human genome. Annu. Rev. Genomics Hum. Genet. 7, 29–59 (2006)
   Article CAS Google Scholar
4. Kim, T. H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005)
   Article ADS CAS Google Scholar
5. Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genet. 39, 311–318 (2007)
   Article CAS Google Scholar
6. Kim, T. H. et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231–1245 (2007)
   Article CAS Google Scholar
7. ENCODE Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004)
8. Xi, H. et al. Identification and characterization of cell type-specific and ubiquitous chromatin regulatory structures in the human genome. PLoS Genet. 3, e136 (2007)
   Article Google Scholar
9. Wang, Q., Carroll, J. S. & Brown, M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol. Cell 19, 631–642 (2005)
   Article CAS Google Scholar
10. Koch, C. M. et al. The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res. 17, 691–707 (2007)
    Article CAS Google Scholar
11. King, D. C. et al. Evaluation of regulatory potential and conservation scores for detecting _cis_-regulatory modules in aligned mammalian genome sequences. Genome Res. 15, 1051–1060 (2005)
    Article CAS Google Scholar
12. Kleinjan, D. A. et al. Aniridia-associated translocations, DNase hypersensitivity, sequence comparison and transgenic analysis redefine the functional domain of PAX6. Hum. Mol. Genet. 10, 2049–2059 (2001)
    Article CAS Google Scholar
13. Wolf, A. T., Medcalf, R. L. & Jern, C. The t-PA -7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid. Blood 105, 1060–1067 (2005)
    Article CAS Google Scholar
14. Xie, X. et al. Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434, 338–345 (2005)
    Article ADS CAS Google Scholar
15. Schug, J. et al. Promoter features related to tissue specificity as measured by Shannon entropy. Genome Biol. 6, R33 (2005)
    Article Google Scholar
16. Carroll, J. S. et al. Genome-wide analysis of estrogen receptor binding sites. Nature Genet. 38, 1289–1297 (2006)
    Article CAS Google Scholar
17. Wei, C. L. et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124, 207–219 (2006)
    Article CAS Google Scholar
18. Yang, A. et al. Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol. Cell 24, 593–602 (2006)
    Article CAS Google Scholar
19. Johnson, D. S., Mortazavi, A., Myers, R. M. & Wold, B. Genome-wide mapping of in vivo protein-DNA interactions. Science 316, 1497–1502 (2007)
    Article ADS CAS Google Scholar
20. Brivanlou, A. H. & Darnell, J. E. Signal transduction and the control of gene expression. Science 295, 813–818 (2002)
    Article ADS CAS Google Scholar
21. Robertson, G. et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nature Methods 4, 651–657 (2007)
    Article CAS Google Scholar
22. Ludwig, T. E. et al. Feeder-independent culture of human embryonic stem cells. Nature Methods 3, 637–646 (2006)
    Article CAS Google Scholar
23. Crawford, G. E. et al. DNase-chip: a high-resolution method to identify DNase I hypersensitive sites using tiled microarrays. Nature Methods 3, 503–509 (2006)
    Article CAS Google Scholar
24. Song, J. S. et al. Model-based analysis of two-color arrays (MA2C). Genome Biol. 8, R178 (2007)
    Article Google Scholar
25. Kheradpour, P., Stark, A., Roy, S. & Kellis, M. Reliable prediction of regulator targets using 12 Drosophila genomes. Genome Res. 17, 1919–1931 (2007)
    Article CAS Google Scholar

Download references

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.

Author information

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

Authors

1. Nathaniel D. Heintzman
   You can also search for this author inPubMed Google Scholar
2. Gary C. Hon
   You can also search for this author inPubMed Google Scholar
3. R. David Hawkins
   You can also search for this author inPubMed Google Scholar
4. Pouya Kheradpour
   You can also search for this author inPubMed Google Scholar
5. Alexander Stark
   You can also search for this author inPubMed Google Scholar
6. Lindsey F. Harp
   You can also search for this author inPubMed Google Scholar
7. Zhen Ye
   You can also search for this author inPubMed Google Scholar
8. Leonard K. Lee
   You can also search for this author inPubMed Google Scholar
9. Rhona K. Stuart
   You can also search for this author inPubMed Google Scholar
10. Christina W. Ching
    You can also search for this author inPubMed Google Scholar
11. Keith A. Ching
    You can also search for this author inPubMed Google Scholar
12. Jessica E. Antosiewicz-Bourget
    You can also search for this author inPubMed Google Scholar
13. Hui Liu
    You can also search for this author inPubMed Google Scholar
14. Xinmin Zhang
    You can also search for this author inPubMed Google Scholar
15. Roland D. Green
    You can also search for this author inPubMed Google Scholar
16. Victor V. Lobanenkov
    You can also search for this author inPubMed Google Scholar
17. Ron Stewart
    You can also search for this author inPubMed Google Scholar
18. James A. Thomson
    You can also search for this author inPubMed Google Scholar
19. Gregory E. Crawford
    You can also search for this author inPubMed Google Scholar
20. Manolis Kellis
    You can also search for this author inPubMed Google Scholar
21. Bing Ren
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toBing 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)

PowerPoint slides

Rights and permissions

About this article

Cite this article

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

Download citation

• Received: 17 October 2008
• Accepted: 26 January 2009
• Published: 18 March 2009
• Issue Date: 07 May 2009
• DOI: https://doi.org/10.1038/nature07829