Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome

Nature Genetics volume 39, pages 311–318 (2007)Cite this article

Abstract

Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Features of human transcriptional promoters and enhancers.
Figure 2: Prediction of promoters based on chromatin signatures.
Figure 3: Prediction of enhancers based on chromatin signatures.
Figure 4: Identification of a putative novel enhancer for SLC22A5.
Figure 5: Validation of the prediction model by STAT1 binding and reporter assays.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Lemon, B. & Tjian, R. Orchestrated response: a symphony of transcription factors for gene control. Genes Dev. 14, 2551–2569 (2000).

    Article  CAS  Google Scholar 

  2. Orphanides, G. & Reinberg, D. A unified theory of gene expression. Cell 108, 439–451 (2002).

    Article  CAS  Google Scholar 

  3. 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 

  4. Smale, S.T. & Kadonaga, J.T. The RNA polymerase II core promoter. Annu. Rev. Biochem. 72, 449–479 (2003).

    Article  CAS  Google Scholar 

  5. Blackwood, E.M. & Kadonaga, J.T. Going the distance: a current view of enhancer action. Science 281, 60–63 (1998).

    Article  CAS  Google Scholar 

  6. Bulger, M. & Groudine, M. Looping versus linking: toward a model for long-distance gene activation. Genes Dev. 13, 2465–2477 (1999).

    Article  CAS  Google Scholar 

  7. Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  Google Scholar 

  8. Margueron, R., Trojer, P. & Reinberg, D. The key to development: interpreting the histone code? Curr. Opin. Genet. Dev. 15, 163–176 (2005).

    Article  CAS  Google Scholar 

  9. Barrera, L.O. & Ren, B. The transcriptional regulatory code of eukaryotic cells - insights from genome-wide analysis of chromatin organization and transcription factor binding. Curr. Opin. Cell. Biol. 18, 291–298 (2006).

    Article  CAS  Google Scholar 

  10. Hatzis, P. & Talianidis, I. Dynamics of enhancer-promoter communication during differentiation-induced gene activation. Mol. Cell 10, 1467–1477 (2002).

    Article  CAS  Google Scholar 

  11. 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 

  12. Bernstein, B.E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).

    Article  CAS  Google Scholar 

  13. Roh, T.Y., Cuddapah, S. & Zhao, K. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. Genes Dev. 19, 542–552 (2005).

    Article  CAS  Google Scholar 

  14. Kim, T.H. & Ren, B. Genome-wide analysis of protein-DNA interactions. Annu. Rev. Genomics Hum. Genet. 7, 81–102 (2006).

    Article  Google Scholar 

  15. The ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004).

  16. Horvai, A.E. et al. Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300. Proc. Natl. Acad. Sci. USA 94, 1074–1079 (1997).

    Article  CAS  Google Scholar 

  17. Pokholok, D.K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005).

    Article  CAS  Google Scholar 

  18. Kim, T.H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005).

    Article  CAS  Google Scholar 

  19. Pruitt, K.D., Tatusova, T. & Maglott, D.R. NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 33, D501–D504 (2005).

    Article  CAS  Google Scholar 

  20. Kouskouti, A. & Talianidis, I. Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J. 24, 347–357 (2005).

    Article  CAS  Google Scholar 

  21. Liu, C.L. et al. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS Biol. 3, e328 (2005).

    Article  Google Scholar 

  22. Harrow, J. et al. GENCODE: producing a reference annotation for ENCODE. Genome Biol. 7 (Suppl.), S4.1–S4.9 (2006).

    Google Scholar 

  23. Felsenfeld, G. Chromatin unfolds. Cell 86, 13–19 (1996).

    Article  CAS  Google Scholar 

  24. Crawford, G.E. et al. DNase-chip: a high-resolution method to identify DNase I hypersensitive sites using tiled microarrays. Nat. Methods 3, 503–509 (2006).

    Article  CAS  Google Scholar 

  25. Blanchette, M. et al. Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression. Genome Res. 16, 656–668 (2006).

    Article  CAS  Google Scholar 

  26. Carninci, P. et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nat. Genet. 38, 626–635 (2006).

    Article  CAS  Google Scholar 

  27. Li, Q., Peterson, K.R., Fang, X. & Stamatoyannopoulos, G. Locus control regions. Blood 100, 3077–3086 (2002).

    Article  CAS  Google Scholar 

  28. Schomig, E. et al. Molecular cloning and characterization of two novel transport proteins from rat kidney. FEBS Lett. 425, 79–86 (1998).

    Article  CAS  Google Scholar 

  29. Sekine, T. et al. Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine. Biochem. Biophys. Res. Commun. 251, 586–591 (1998).

    Article  CAS  Google Scholar 

  30. Tamai, I. et al. Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J. Biol. Chem. 273, 20378–20382 (1998).

    Article  CAS  Google Scholar 

  31. Wu, X., Prasad, P.D., Leibach, F.H. & Ganapathy, V. cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem. Biophys. Res. Commun. 246, 589–595 (1998).

    Article  CAS  Google Scholar 

  32. Nezu, J. et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat. Genet. 21, 91–94 (1999).

    Article  CAS  Google Scholar 

  33. Shoji, Y. et al. Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q. Am. J. Hum. Genet. 63, 101–108 (1998).

    Article  CAS  Google Scholar 

  34. Stanley, C.A. Carnitine deficiency disorders in children. Ann. NY Acad. Sci. 1033, 42–51 (2004).

    Article  CAS  Google Scholar 

  35. Wang, Y., Ye, J., Ganapathy, V. & Longo, N. Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. Proc. Natl. Acad. Sci. USA 96, 2356–2360 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Kadonaga, X. Fu and members of the Ren lab for comments. This work was supported by funding from the Ludwig Institute for Cancer Research (B.R.), the National Human Genome Research Institute (B.R., Z.W. and R.D.G.) and the National Cancer Institute (B.R.). Requests for materials should be addressed to B.R.

Author information

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, 92093-0653, California, USA

    Nathaniel D Heintzman, Rhona K Stuart, Gary Hon, Christina W Ching, R David Hawkins, Leah O Barrera, Sara Van Calcar, Chunxu Qu, Keith A Ching & Bing Ren

  2. Biomedical Sciences Graduate Program, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, 92093-0653, California, USA

    Nathaniel D Heintzman

  3. Program in Bioinformatics and University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653 USA.,

    Gary Hon & Leah O Barrera

  4. Bioinformatics Program, Boston University, 24 Cummington Street, 1002, Boston, 02215, Massachusetts, USA

    Yutao Fu & Zhiping Weng

  5. Department of Chemistry and Biochemistry, UCSD, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Wei Wang

  6. Biomedical Engineering Department, Boston University, 44 Cummington Street, Boston, 02215, MA

    Zhiping Weng

  7. NimbleGen Systems, Inc., 1 Science Court, Madison, 53711, Wisconsin, USA

    Roland D Green

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

    Gregory E Crawford

  9. Department of Cellular and Molecular Medicine, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, 92093-0653, California, USA

    Bing Ren

Authors
  1. Nathaniel D Heintzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rhona K Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary Hon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yutao Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christina W Ching
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R David Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leah O Barrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sara Van Calcar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chunxu Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keith A Ching
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zhiping Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Roland D Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Gregory E Crawford
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Bing Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.D.H., B.R. and R.D.G. designed the transcription factor and histone ChIP-chip experiments; G.E.C. designed and performed the DNase-chip experiments; N.D.H., R.K.S., C.W.C., R.D.H. and S.V.C. conducted the ChIP-chip experiments; N.D.H., G.H., L.O.B., K.A.C. and C.Q. analyzed the microarray data; G.H., N.D.H., B.R. and W.W. conceived and developed the promoter and enhancer prediction method. Independently, Y.F. and Z.W. discovered the promoter-associated chromatin signatures. N.D.H. and B.R. wrote the manuscript.

Corresponding author

Correspondence to Bing Ren.

Ethics declarations

Competing interests

R.D.G. is an employee of NimbleGen Systems, Inc.

Supplementary information

Supplementary Fig. 1

ChIP-chip profiles at a representative promoter. (PDF 336 kb)

Supplementary Fig. 2

Cluster analysis in IFNγ-treated HeLa cells. (PDF 600 kb)

Supplementary Fig. 3

p300 binding distribution and DNaseI hypersensitivity. (PDF 330 kb)

Supplementary Fig. 4

Distribution of predicted enhancers in IFNγ-treated HeLa cells. (PDF 293 kb)

Supplementary Fig. 5

Prediction of a known enhancer, HS2, in the human β-globin locus. (PDF 371 kb)

Supplementary Fig. 6

Cross-validation of optimal histone modifications for prediction model. (PDF 362 kb)

Supplementary Table 1

Summary of RNAP ChIP-chip validation. (XLS 32 kb)

Supplementary Table 2

TSS classes from promoter clustering. (XLS 101 kb)

Supplementary Table 3

p300 binding sites. (XLS 69 kb)

Supplementary Table 4

DNaseI hypersensitive sites. (XLS 109 kb)

Supplementary Table 5

High-confidence prediction sets. (XLS 388 kb)

Supplementary Table 6

TRAP220 binding sites. (XLS 36 kb)

Supplementary Table 7

STAT1 binding sites. (XLS 24 kb)

Supplementary Methods (PDF 135 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heintzman, N., Stuart, R., Hon, G. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39, 311–318 (2007). https://doi.org/10.1038/ng1966

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1966

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing