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Genome-wide maps of chromatin state in pluripotent and lineage-committed cells

Naturevolume 448, pages553–560 (2007)Cite this article

Abstract

We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells. By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts. We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation. Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions. Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.

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Figure 1:Comparison of ChIP-Seq and ChIP-chip data.
Figure 2:Histone trimethylation state predicts expression of HCPs and LCPs.
Figure 3:Cell-type-specific chromatin marks at promoters.
Figure 4:Correlation between chromatin-state changes and lineage expression.
Figure 5:H3K4me3 and H3K36me3 annotate genes and non-coding RNA transcripts.
Figure 6:Allele-specific histone methylation and genic H3K9me3/H4K20me3.

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References

  1. Surani, M. A., Hayashi, K. & Hajkova, P. Genetic and epigenetic regulators of pluripotency.Cell128, 747–762 (2007)

    Article CAS  Google Scholar 

  2. Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome.Cell128, 669–681 (2007)

    Article CAS  Google Scholar 

  3. Kouzarides, T. Chromatin modifications and their function.Cell128, 693–705 (2007)

    Article CAS  Google Scholar 

  4. Buck, M. J. & Lieb, J. D. ChIP-chip: considerations for the design, analysis, and application of genome-wide chromatin immunoprecipitation experiments.Genomics83, 349–360 (2004)

    Article CAS  Google Scholar 

  5. Mockler, T. C. et al. Applications of DNA tiling arrays for whole-genome analysis.Genomics85, 1–15 (2005)

    Article CAS  Google Scholar 

  6. 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 

  7. Service, R. F. Gene sequencing. The race for the $1000 genome.Science311, 1544–1546 (2006)

    Article CAS  Google Scholar 

  8. Conti, L. et al. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell.PLoS Biol.3, e283 (2005)

    Article  Google Scholar 

  9. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells.Cell125, 315–326 (2006)

    Article CAS  Google Scholar 

  10. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins.Annu. Rev. Genet.38, 413–443 (2004)

    Article CAS  Google Scholar 

  11. Schuettengruber, B., Chourrout, D., Vervoort, M., Leblanc, B. & Cavalli, G. Genome regulation by polycomb and trithorax proteins.Cell128, 735–745 (2007)

    Article CAS  Google Scholar 

  12. Azuara, V. et al. Chromatin signatures of pluripotent cell lines.Nature Cell Biol.8, 532–538 (2006)

    Article CAS  Google Scholar 

  13. Saxonov, S., Berg, P. & Brutlag, D. L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters.Proc. Natl Acad. Sci. USA103, 1412–1417 (2006)

    Article ADS CAS  Google Scholar 

  14. Weber, M. et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.Nature Genet.39, 457–466 (2007)

    Article CAS  Google Scholar 

  15. Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse.Cell120, 169–181 (2005)

    Article CAS  Google Scholar 

  16. Kim, T. H. et al. A high-resolution map of active promoters in the human genome.Nature436, 876–880 (2005)

    Article ADS CAS  Google Scholar 

  17. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells.Nature441, 349–353 (2006)

    Article ADS CAS  Google Scholar 

  18. Lee, T. I. et al. Control of developmental regulators by polycomb in human embryonic stem cells.Cell125, 301–313 (2006)

    Article CAS  Google Scholar 

  19. Squazzo, S. L. et al. Suz12 binds to silenced regions of the genome in a cell-type-specific manner.Genome Res.16, 890–900 (2006)

    Article CAS  Google Scholar 

  20. Pasini, D., Bracken, A. P., Hansen, J. B., Capillo, M. & Helin, K. The Polycomb Group protein Suz12 is required for Embryonic Stem Cell differentiation.Mol. Cell. Biol.27, 3769–3779 (2007)

    Article CAS  Google Scholar 

  21. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators.Trends Biochem. Sci.31, 89–97 (2006)

    Article CAS  Google Scholar 

  22. Wang, X., Su, H. & Bradley, A. Molecular mechanisms governingPcdh-γ gene expression: evidence for a multiple promoter andcis-alternative splicing model.Genes Dev.16, 1890–1905 (2002)

    Article CAS  Google Scholar 

  23. Carninci, P. et al. The transcriptional landscape of the mammalian genome.Science309, 1559–1563 (2005)

    Article ADS CAS  Google Scholar 

  24. Alexander, D. L., Ganem, L. G., Fernandez-Salguero, P., Gonzalez, F. & Jefcoate, C. R. Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis.J. Cell Sci.111, 3311–3322 (1998)

    CAS PubMed  Google Scholar 

  25. Lengner, C. J. et al. Primary mouse embryonic fibroblasts: a model of mesenchymal cartilage formation.J. Cell. Physiol.200, 327–333 (2004)

    Article CAS  Google Scholar 

  26. Garreta, E., Genove, E., Borros, S. & Semino, C. E. Osteogenic differentiation of mouse embryonic stem cells and mouse embryonic fibroblasts in a three-dimensional self-assembling peptide scaffold.Tissue Eng.12, 2215–2227 (2006)

    Article CAS  Google Scholar 

  27. Doetsch, F. The glial identity of neural stem cells.Nature Neurosci.6, 1127–1134 (2003)

    Article CAS  Google Scholar 

  28. Krichevsky, A. M., Sonntag, K. C., Isacson, O. & Kosik, K. S. Specific microRNAs modulate embryonic stem cell-derived neurogenesis.Stem Cells24, 857–864 (2006)

    Article CAS  Google Scholar 

  29. Rao, B., Shibata, Y., Strahl, B. D. & Lieb, J. D. Dimethylation of histone H3 at lysine 36 demarcates regulatory and nonregulatory chromatin genome-wide.Mol. Cell. Biol.25, 9447–9459 (2005)

    Article CAS  Google Scholar 

  30. Bannister, A. J. et al. Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes.J. Biol. Chem.280, 17732–17736 (2005)

    Article CAS  Google Scholar 

  31. Kim, A., Kiefer, C. M. & Dean, A. Distinctive signatures of histone methylation in transcribed coding and noncoding human β-globin sequences.Mol. Cell. Biol.27, 1271–1279 (2007)

    Article CAS  Google Scholar 

  32. Vakoc, C. R., Sachdeva, M. M., Wang, H. & Blobel, G. A. Profile of histone lysine methylation across transcribed mammalian chromatin.Mol. Cell. Biol.26, 9185–9195 (2006)

    Article CAS  Google Scholar 

  33. Li, B., Carey, M. & Workman, J. L. The role of chromatin during transcription.Cell128, 707–719 (2007)

    Article CAS  Google Scholar 

  34. Fantes, J. et al. Mutations inSOX2 cause anophthalmia.Nature Genet.33, 461–463 (2003)

    Article CAS  Google Scholar 

  35. Hutchinson, J. N. et al. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains.BMC Genomics8, 39 (2007)

    Article  Google Scholar 

  36. Seitz, H. et al. A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain.Genome Res.14, 1741–1748 (2004)

    Article CAS  Google Scholar 

  37. Cullen, B. R. Transcription and processing of human microRNA precursors.Mol. Cell16, 861–865 (2004)

    Article CAS  Google Scholar 

  38. Zaratiegui, M., Irvine, D. V. & Martienssen, R. A. Noncoding RNAs and gene silencing.Cell128, 763–776 (2007)

    Article CAS  Google Scholar 

  39. Verdel, A. & Moazed, D. RNAi-directed assembly of heterochromatin in fission yeast.FEBS Lett.579, 5872–5878 (2005)

    Article CAS  Google Scholar 

  40. Martens, J. H. et al. The profile of repeat-associated histone lysine methylation states in the mouse epigenome.EMBO J.24, 800–812 (2005)

    Article CAS  Google Scholar 

  41. Baust, C. et al. Structure and expression of mobile ETnII retroelements and their coding-competent MusD relatives in the mouse.J. Virol.77, 11448–11458 (2003)

    Article CAS  Google Scholar 

  42. Svoboda, P. et al. RNAi and expression of retrotransposons MuERV-L and IAP in preimplantation mouse embryos.Dev. Biol.269, 276–285 (2004)

    Article CAS  Google Scholar 

  43. Cho, D. H. et al. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF.Mol. Cell20, 483–489 (2005)

    Article CAS  Google Scholar 

  44. Feng, Y. Q. et al. The human β-globin locus control region can silence as well as activate gene expression.Mol. Cell. Biol.25, 3864–3874 (2005)

    Article CAS  Google Scholar 

  45. Edwards, C. A. & Ferguson-Smith, A. C. Mechanisms regulating imprinted genes in clusters.Curr. Opin. Cell Biol.19, 281–289 (2007)

    Article CAS  Google Scholar 

  46. Delaval, K. et al. Differential histone modifications mark mouse imprinting control regions during spermatogenesis.EMBO J.26, 720–729 (2007)

    Article CAS  Google Scholar 

  47. Feil, R. & Berger, F. Convergent evolution of genomic imprinting in plants and mammals.Trends Genet.23, 192–199 (2007)

    Article CAS  Google Scholar 

  48. Strausberg, R. L. et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.Proc. Natl Acad. Sci. USA99, 16899–16903 (2002)

    Article ADS  Google Scholar 

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Acknowledgements

We thank S. Fisher, M. Kellis, B. Birren and M. Zody for technical assistance and constructive discussions. We acknowledge L. Zagachin in the MGH Nucleic Acid Quantitation core for assistance with real-time PCR. E.M. was supported by an institutional training grant from NIH. M.W. was supported by fellowships from the Human Frontiers Science Organization Program and the Ellison Foundation. This research was supported by funds from the National Human Genome Research Institute, the National Cancer Institute, the Burroughs Wellcome Fund, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard.

All analysed data sets can be obtained fromhttp://www.broad.mit.edu/seq_platform/chip/. Microarray data have been submitted to the GEO repository under accession number GSE8024.

Author information

Author notes

  1. Eric S. Lander and Bradley E. Bernstein: These authors contributed equally to this work.

Authors and Affiliations

  1. Broad Institute of Harvard and MIT,,

    Tarjei S. Mikkelsen, Manching Ku, David B. Jaffe, Biju Issac, Erez Lieberman, Georgia Giannoukos, Pablo Alvarez, William Brockman, Richard P. Koche, William Lee, Eric Mendenhall, Aviva Presser, Carsten Russ, Xiaohui Xie, Chad Nusbaum, Eric S. Lander & Bradley E. Bernstein

  2. Division of Health Sciences and Technology, MIT, and,

    Tarjei S. Mikkelsen, Erez Lieberman & Richard P. Koche

  3. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA,

    Alexander Meissner, Marius Wernig, Rudolf Jaenisch & Eric S. Lander

  4. Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA,

    Manching Ku, Biju Issac, Richard P. Koche, Eric Mendenhall, Aisling O’Donovan & Bradley E. Bernstein

  5. Department of Neurology, Children’s Hospital, and,

    Tae-Kyung Kim

  6. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Bradley E. Bernstein

Authors
  1. Tarjei S. Mikkelsen
  2. Manching Ku
  3. David B. Jaffe
  4. Biju Issac
  5. Erez Lieberman
  6. Georgia Giannoukos
  7. Pablo Alvarez
  8. William Brockman
  9. Tae-Kyung Kim
  10. Richard P. Koche
  11. William Lee
  12. Eric Mendenhall
  13. Aisling O’Donovan
  14. Aviva Presser
  15. Carsten Russ
  16. Xiaohui Xie
  17. Alexander Meissner
  18. Marius Wernig
  19. Rudolf Jaenisch
  20. Chad Nusbaum
  21. Eric S. Lander
  22. Bradley E. Bernstein

Corresponding authors

Correspondence toEric S. Lander orBradley E. Bernstein.

Ethics declarations

Competing interests

Reprints and permissions information is available atwww.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Notes which includes the ChIP-Seq read requirement, genome coverage and accuracy and Supplementary Figures 1-10 with Legends (PDF 9260 kb)

Supplementary Table 1

This file contains Supplementary Table 1 which includes the list of datasets analyzed. (XLS 15 kb)

Supplementary Table 2

This file contains Supplementary Table 2 which includes the primers for RT-PCR validation of ChIP-Seq. (XLS 24 kb)

Supplementary Table 3

This file contains Supplementary Table 3 which includes the list of analyzed promoters and their chromatin state in ES cells, neural progenitors and embryonic fibroblasts. (XLS 3206 kb)

Supplementary Table 4

This file contains Supplementary Table 4 which includes the expression levels for analyzed genes in ES cells, neural progenitors and embryonic fibroblasts. (XLS 2070 kb)

Supplementary Table 5

This file contains Supplementary Table 5 which includes the Gene Ontology categories associated with monovalent and bivalent promoters in ES cells. (XLS 35 kb)

Supplementary Table 6

This file contains Supplementary Table 6 which includes the chromatin state of promoters associated with known regulators or markers of differentiated cell types (XLS 23 kb)

Supplementary Table 7

This file contains Supplementary Table 7 which includes the allelic bias observed at verified or putative imprinting control regions. (XLS 21 kb)

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Mikkelsen, T., Ku, M., Jaffe, D.et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.Nature448, 553–560 (2007). https://doi.org/10.1038/nature06008

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Editorial Summary

Chromatin profiling

Although they contain the same set of genes, different cell types in a multicellular organism maintain very different behaviours. These cell states are thought to be related to chromatin state — that is, modifications to histones and other proteins that package the genome. Single-molecule sequencing technology has now been used to construct chromatin-state maps for mouse embryonic stem cells and two other more developmentally advanced cell types, revealing the genome-wide distribution of important chromatin modifications. The study provides pointers for the use of chromatin profiling on mammalian cell populations, including those of abnormal cells, such as cancer.

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