This article has been updated

Abstract

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Change history

  • 23 March 2011

    Author initials were corrected for T.K.C.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 10.1126/science.1198374. (in the press)

  2. 2.

    et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 10.1126/science.1196914. (in the press)

  3. 3.

    et al. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195 (2000)

  4. 4.

    et al. Evolution of genes and genomes on the Drosophila phylogeny. Nature 450, 203–218 (2007)

  5. 5.

    et al. Sequence finishing and mapping of Drosophila melanogaster heterochromatin. Science 316, 1625–1628 (2007)

  6. 6.

    et al. FlyBase: enhancing Drosophila Gene Ontology annotations. Nucleic Acids Res. 37, D555–D559 (2009)

  7. 7.

    & Controlling the double helix. Nature 421, 448–453 (2003)

  8. 8.

    & Chromatin state maps: new technologies, new insights. Curr. Opin. Genet. Dev. 18, 109–115 (2008)

  9. 9.

    et al. An assessment of histone-modification antibody quality. Nature Struct. Mol. Biol. 10.1038/nsmb.1972 (5 December 2010)

  10. 10.

    & Cellular mechanism for targeting heterochromatin formation in Drosophila. Int. Rev. Cell Mol. Biol. 273, 1–47 (2009)

  11. 11.

    & Polycomb complexes and epigenetic states. Curr. Opin. Cell Biol. 20, 266–273 (2008)

  12. 12.

    , & The role of chromatin during transcription. Cell 128, 707–719 (2007)

  13. 13.

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

  14. 14.

    et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007)

  15. 15.

    et al. MSL complex is attracted to genes marked by H3K36 trimethylation using a sequence-independent mechanism. Mol. Cell 28, 121–133 (2007)

  16. 16.

    et al. Plasticity in patterns of histone modifications and chromosomal proteins in Drosophila heterochromatin. Genome Res. 10.1101/gr.110098.110. (in the press)

  17. 17.

    Visualization of genomic data with the Hilbert curve. Bioinformatics 25, 1231–1235 (2009)

  18. 18.

    , & Coordination of replication and transcription along a Drosophila chromosome. Genes Dev. 18, 3094–3105 (2004)

  19. 19.

    , & The units of DNA replication in Drosophila melanogaster chromosomes. Cold Spring Harb. Symp. Quant. Biol. 38, 205–223 (1974)

  20. 20.

    & Discovery and characterization of chromatin states for systematic annotation of the human genome. Nature Biotechnol. 28, 817–825 (2010)

  21. 21.

    et al. Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome. Chromosoma 117, 89–102 (2008)

  22. 22.

    et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010)

  23. 23.

    , & Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science 328, 1161–1164 (2010)

  24. 24.

    , , , & Genome-wide profiling of salt fractions maps physical properties of chromatin. Genome Res. 19, 460–469 (2009)

  25. 25.

    , , , & Drosophila ORC localizes to open chromatin and marks sites of cohesin complex loading. Genome Res. 20, 201–211 (2010)

  26. 26.

    et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009)

  27. 27.

    , , , & Combinatorial binding predicts spatio-temporal cis-regulatory activity. Nature 462, 65–70 (2009)

  28. 28.

    et al. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nature Genet. 38, 700–705 (2006)

  29. 29.

    et al. Alternative epigenetic chromatin states of Polycomb target genes. PLoS Genet. 6, e1000805 (2010)

  30. 30.

    et al. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327, 335–338 (2010)

  31. 31.

    , & Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008)

  32. 32.

    The 5′ ends of Drosophila heat shock genes in chromatin are hypersensitive to DNase I. Nature 286, 854–860 (1980)

  33. 33.

    , , , & The chromatin structure of specific genes: I. Evidence for higher order domains of defined DNA sequence. Cell 16, 797–806 (1979)

  34. 34.

    The formation and function of DNase I hypersensitive sites in the process of gene activation. J. Biol. Chem. 263, 19259–19262 (1988)

  35. 35.

    et al. H3.3/H2A.Z double variant-containing nucleosomes mark ‘nucleosome-free regions’ of active promoters and other regulatory regions. Nature Genet. 41, 941–945 (2009)

  36. 36.

    et al. Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nature Methods 6, 283–289 (2009)

  37. 37.

    et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009)

  38. 38.

    et al. Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions. Genome Biol. 10, R80 (2009)

  39. 39.

    et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010)

  40. 40.

    et al. Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143, 212–224 (2010)

  41. 41.

    et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006)

  42. 42.

    et al. Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol. Cell 38, 675–688 (2010)

  43. 43.

    et al. Functional anatomy of polycomb and trithorax chromatin landscapes in Drosophila embryos. PLoS Biol. 7, e13 (2009)

  44. 44.

    et al. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-γ locus. Immunity 31, 551–564 (2009)

  45. 45.

    et al. The transcriptional diversity of 25 Drosophila cell lines. Genome Res. 21 10.1101/gr.112961.110 (in the press)

  46. 46.

    et al. The developmental transcriptome of Drosophila melanogaster. Nature 10.1038/nature09715 (this issue).

  47. 47.

    et al. Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc. Natl Acad. Sci. USA 97, 6499–6503 (2000)

Download references

Acknowledgements

We thank our technicians D. Acevedo, S. Gadel, C. Kennedy, O.-K. Lee, S. Marchetti, S. Vong and M. Weaver, and Rutgers BRTC. We also thank our colleagues who donated antibodies: J. Kadonaga (H1), A. L. Greenleaf (RNA pol II), G. Reuter (SU(VAR)3-9), G. Cavalli (GAF) and I. F. Zhimulev/H. Saumweber (Chromator). The major support for this work came from the modENCODE grant U01HG004258 to G.H.K. (Principal Investigator) and S.C.R.E., M.I.K., P.J.P. and V.P. (co-Principal Investigators), administered under Department of Energy contract no. DE-AC02-05CH11231. Additional funding came from RC2 HG005639, U01 HG004279, R01 GM082798, R37 GM45744, RC1 HG005334, R01 GM071923, U54 HG004592 and NSF 0905968.

Author information

Author notes

    • Yuri B. Schwartz
    • , Daniela Linder-Basso
    •  & Gregory Shanower

    Present addresses: Department of Molecular Biology, Umea University, 901 87 Umea, Sweden. (Y.B.S.); Department of Plant Biology and Pathology, SEBS, Rutgers University, New Brunswick, New Jersey 08901, USA (D.L.-B.); Department of Basic Sciences, The Commonwealth Medical College, Scranton, Pennsylvania 18510, USA (G.S.).

    • Gary H. Karpen
    •  & Peter J. Park

    These authors contributed equally to this work.

Affiliations

  1. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Peter V. Kharchenko
    • , Michael Y. Tolstorukov
    • , Lovelace J. Luquette
    • , Ruibin Xi
    • , Youngsook L. Jung
    • , Richard W. Park
    • , Eric P. Bishop
    •  & Peter J. Park
  2. Children’s Hospital Informatics Program, Boston, Massachusetts 02115, USA

    • Peter V. Kharchenko
    • , Michael Y. Tolstorukov
    •  & Peter J. Park
  3. Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA

    • Artyom A. Alekseyenko
    • , Erica Larschan
    • , Andrey A. Gorchakov
    • , Annette Plachetka
    • , Youngsook L. Jung
    • , Mitzi I. Kuroda
    •  & Peter J. Park
  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Artyom A. Alekseyenko
    • , Erica Larschan
    • , Andrey A. Gorchakov
    • , Annette Plachetka
    •  & Mitzi I. Kuroda
  5. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA

    • Yuri B. Schwartz
    • , Daniela Linder-Basso
    • , Gregory Shanower
    •  & Vincenzo Pirrotta
  6. Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA

    • Aki Minoda
    •  & Gary H. Karpen
  7. Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA

    • Nicole C. Riddle
    • , Tingting Gu
    •  & Sarah C. R. Elgin
  8. MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA

    • Jason Ernst
    •  & Manolis Kellis
  9. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Jason Ernst
    •  & Manolis Kellis
  10. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA

    • Peter J. Sabo
    • , Theresa K. Canfield
    • , Richard Sandstrom
    • , Robert E. Thurman
    •  & John A. Stamatoyannopoulos
  11. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02906, USA

    • Erica Larschan
  12. Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts 02115, USA

    • Richard W. Park
    •  & Eric P. Bishop
  13. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • David M. MacAlpine
  14. Department of Medicine, University of Washington, Seattle, Washington 98195, USA

    • John A. Stamatoyannopoulos

Authors

  1. Search for Peter V. Kharchenko in:

  2. Search for Artyom A. Alekseyenko in:

  3. Search for Yuri B. Schwartz in:

  4. Search for Aki Minoda in:

  5. Search for Nicole C. Riddle in:

  6. Search for Jason Ernst in:

  7. Search for Peter J. Sabo in:

  8. Search for Erica Larschan in:

  9. Search for Andrey A. Gorchakov in:

  10. Search for Tingting Gu in:

  11. Search for Daniela Linder-Basso in:

  12. Search for Annette Plachetka in:

  13. Search for Gregory Shanower in:

  14. Search for Michael Y. Tolstorukov in:

  15. Search for Lovelace J. Luquette in:

  16. Search for Ruibin Xi in:

  17. Search for Youngsook L. Jung in:

  18. Search for Richard W. Park in:

  19. Search for Eric P. Bishop in:

  20. Search for Theresa K. Canfield in:

  21. Search for Richard Sandstrom in:

  22. Search for Robert E. Thurman in:

  23. Search for David M. MacAlpine in:

  24. Search for John A. Stamatoyannopoulos in:

  25. Search for Manolis Kellis in:

  26. Search for Sarah C. R. Elgin in:

  27. Search for Mitzi I. Kuroda in:

  28. Search for Vincenzo Pirrotta in:

  29. Search for Gary H. Karpen in:

  30. Search for Peter J. Park in:

Contributions

P.V.K. performed most bioinformatic analysis. A.A.A., Y.B.S., A.M., N.C.R., E.L., A.A.G., T.G., D.L.-B., A.P. and G.S. generated data, directed by S.C.R.E., M.I.K., V.P. and G.H.K. The 30-state analysis was performed by J.E. and M.K., whereas M.Y.T., L.J.L., R.X., Y.L.J., R.W.P. and E.P.B. performed additional bioinformatic analysis. P.J.S., T.K.C., R.S., R.E.T. and J.A.S. generated and processed DHS data. D.M.M. helped with replication analysis. P.J.P. supervised all analysis. G.H.K. coordinated the entire project. P.V.K., G.H.K. and P.J.P. wrote the manuscript, with contributions from S.C.R.E., M.I.K., V.P., Y.B.S, N.C.R, A.A.A. and A.M.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gary H. Karpen or Peter J. Park.

The data are available from the modENCODE site (http://www.modencode.org). GRO-Seq data are available from Gene Expression Omnibus (GEO, GSE25321).

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figures 1-35 with legends.

  2. 2.

    Supplementary Information

    This file contains Supplementary Tables 1-6 and Supplementary Sections 1-2.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature09725

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.