Article | Published:

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

Nature Genetics volume 39, pages 311318 (2007) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Gene Expression Omnibus

References

  1. 1.

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

  2. 2.

    & A unified theory of gene expression. Cell 108, 439–451 (2002).

  3. 3.

    , & Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr. Opin. Genet. Dev. 16, 125–136 (2006).

  4. 4.

    & The RNA polymerase II core promoter. Annu. Rev. Biochem. 72, 449–479 (2003).

  5. 5.

    & Going the distance: a current view of enhancer action. Science 281, 60–63 (1998).

  6. 6.

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

  7. 7.

    & The language of covalent histone modifications. Nature 403, 41–45 (2000).

  8. 8.

    , & The key to development: interpreting the histone code? Curr. Opin. Genet. Dev. 15, 163–176 (2005).

  9. 9.

    & 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).

  10. 10.

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

  11. 11.

    , & Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol. Cell 19, 631–642 (2005).

  12. 12.

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

  13. 13.

    , & Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. Genes Dev. 19, 542–552 (2005).

  14. 14.

    & Genome-wide analysis of protein-DNA interactions. Annu. Rev. Genomics Hum. Genet. 7, 81–102 (2006).

  15. 15.

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

  16. 16.

    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).

  17. 17.

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

  18. 18.

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

  19. 19.

    , & NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 33, D501–D504 (2005).

  20. 20.

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

  21. 21.

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

  22. 22.

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

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

    , , & Locus control regions. Blood 100, 3077–3086 (2002).

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

    , , & 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).

  32. 32.

    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).

  33. 33.

    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).

  34. 34.

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

  35. 35.

    , , & Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. Proc. Natl. Acad. Sci. USA 96, 2356–2360 (1999).

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

Affiliations

  1. Ludwig Institute for Cancer Research, University of California San Diego (UCSD) School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653 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, California 92093-0653 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, Massachusetts 02215 USA.

    • Yutao Fu
    •  & Zhiping Weng
  5. Department of Chemistry and Biochemistry, UCSD, 9500 Gilman Drive, La Jolla, California 92093 USA.

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

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

    • Roland D Green
  8. Institute for Genome Sciences & Policy and Department of Pediatrics, Duke University, 101 Science Drive, Durham, North Carolina 27708, 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, California 92093-0653 USA.

    • Bing Ren

Authors

  1. Search for Nathaniel D Heintzman in:

  2. Search for Rhona K Stuart in:

  3. Search for Gary Hon in:

  4. Search for Yutao Fu in:

  5. Search for Christina W Ching in:

  6. Search for R David Hawkins in:

  7. Search for Leah O Barrera in:

  8. Search for Sara Van Calcar in:

  9. Search for Chunxu Qu in:

  10. Search for Keith A Ching in:

  11. Search for Wei Wang in:

  12. Search for Zhiping Weng in:

  13. Search for Roland D Green in:

  14. Search for Gregory E Crawford in:

  15. Search for Bing Ren in:

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.

Competing interests

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

Corresponding author

Correspondence to Bing Ren.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    ChIP-chip profiles at a representative promoter.

  2. 2.

    Supplementary Fig. 2

    Cluster analysis in IFNγ-treated HeLa cells.

  3. 3.

    Supplementary Fig. 3

    p300 binding distribution and DNaseI hypersensitivity.

  4. 4.

    Supplementary Fig. 4

    Distribution of predicted enhancers in IFNγ-treated HeLa cells.

  5. 5.

    Supplementary Fig. 5

    Prediction of a known enhancer, HS2, in the human β-globin locus.

  6. 6.

    Supplementary Fig. 6

    Cross-validation of optimal histone modifications for prediction model.

  7. 7.

    Supplementary Methods

Excel files

  1. 1.

    Supplementary Table 1

    Summary of RNAP ChIP-chip validation.

  2. 2.

    Supplementary Table 2

    TSS classes from promoter clustering.

  3. 3.

    Supplementary Table 3

    p300 binding sites.

  4. 4.

    Supplementary Table 4

    DNaseI hypersensitive sites.

  5. 5.

    Supplementary Table 5

    High-confidence prediction sets.

  6. 6.

    Supplementary Table 6

    TRAP220 binding sites.

  7. 7.

    Supplementary Table 7

    STAT1 binding sites.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng1966

Further reading